PHARMACEUTICAL CARRIERS CAPABLE OF pH DEPENDENT RECONSTITUTION AND METHODS FOR MAKING AND USING SAME

ABSTRACT

Disclosed herein are novel drug carriers including a non-aqueous pH dependent release system and a non-aqueous pH dependent reassembly/assembly and reabsorption/absorption system. The carriers are capable of pH dependent release of biologically active agents and assembly or reassembly when the carrier transitions from a low pH environment, to a high pH environment and back to a low pH environment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/675,780, filed Feb. 18, 2022, which is a continuation of U.S. patentapplication Ser. No. 17/378,458, filed Jul. 16, 2021, which is acontinuation of International Patent Application No. PCT/US2021/024061,filed Mar. 25, 2021, which claims the benefit of priority from U.S.Provisional Patent Application No. 63/000,287, filed Mar. 26, 2020, thecontents of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE DISCLOSURE

One problem associated with many pharmaceuticals that are injurious tothe stomach or are susceptible to degradation in the stomach is thatsuch pharmaceuticals do not simply proceed from the stomach to the smallintestine, through the pyloric sphincter, and into the duodenum. Rather,a portion of such pharmaceuticals flows backward from the duodenum andthrough the pyloric sphincter, while the sphincter is opened into thestomach (duodenal reflux). Thus, injurious pharmaceuticals contained inthe back flow may cause injury to the lining of the stomach, e.g.,nonsteroidal anti-inflammatory drugs (NSAIDs), while degradablepharmaceuticals may be subject to further loss due to degradation in thestomach, e.g., heparin or insulin.

There is a need in the art for improved pharmaceutical formulations. Thepresent disclosure satisfies this need.

SUMMARY OF THE DISCLOSURE

In one aspect of the disclosure, described are pharmaceutical carriercompositions comprising: (a) a non-aqueous pH dependent release system;and (b) a non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system. The pharmaceutical carrier compositionsare characterized by: (i) the carrier composition has a low pH form anda high pH form; (ii) the carrier composition is formulated to releaseone or more biologically active agents minimally from a low pH form andmaximally from a high pH form due to the non-aqueous pH dependentrelease system; (iii) the carrier composition is formulated to eitherreassemble into the low pH form or assembly into a new low pH form dueto the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system; and (iv) the carrier composition isformulated to either reabsorb the one or more biologically active agentsin its reassembled form or absorb the one or more biologically activeagents in the newly assembled form.

In another aspect, for the compositions of the disclosure, thenon-aqueous pH dependent reassembly/assembly and reabsorption/absorptionsystem comprises one or more nonionic surfactants. For example, the oneor more nonionic surfactants can be present in the composition in anamount of about 0.05 wt. % to about 20 wt. %. Further, the one or morenonionic surfactants can comprise an ethylene glycol mono fatty acidester, a propylene glycol mono fatty acid ester, or a combination of twoor more thereof. In addition, the one or more nonionic surfactants cancomprise (a) one or more selected from sorbitan mono, di, and tri fattyacid esters; and/or (b) propylene glycol monolaurate; and/or (c)sorbitan trioleate (STO), sorbitan monooleate, or sorbitan tristearate,or a combination thereof.

In one aspect, for the compositions of the disclosure, the non-aqueouspH dependent reassembly/assembly and reabsorption/absorption system cancomprise one or more zwittterionic surfactants.

In another aspect, for the compositions of the disclosure, the one ormore zwittterionic surfactants comprise one or more zwittterionicphospholipids. For example, the one or more zwitterionic surfactants cancomprise phosphatidic acid, phosphatidylethanolamine,phosphatidylcholine, phosphatidylserine, phosphatidylinositol,phosphatidylinositol phosphate, phosphatidylinositol bisphosphate,phosphatidylinositol triphosphate, ceramide phosphorylcholine, ceramidephosphorylethanolamine, ceramide phosphorylglycerol,dimyristoylphosphatidylcholine, distearoylphosphatidylcholine,dilinoleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, or acombination of two or more thereof. In another aspect, the one or morezwitterionic surfactants can comprise lecithin.

In a further aspect, for the compositions of the disclosure, the one ormore zwittterionic surfactants can be present in the composition in anamount of at least about 10 wt. %. In another aspect, the one or morezwitterionic surfactants are present in the composition in an amount ofabout 5 wt. % to about 25 wt. %.

In one embodiment, for the compositions of the disclosure, the pHdependent release system can comprise a carboxylic acid having at least8 carbon atoms. In another aspect, the carboxylic acid having at least 8carbon atoms can be present in the composition in an amount of at leastabout 5 wt. %, at least about 10 wt. %, at least about 15 wt. %, atleast about 20 wt. %, or in an amount of about 5 wt. % to about 50 wt.%.

In another embodiment, for the compositions of the disclosure, thecarboxylic acid having at least 8 carbon atoms is a monocarboxylic acid.

In one aspect of the disclosure for the compositions described herein,the carboxylic acid having at least 8 carbon atoms is selected from thegroup consisting of as octenoic acid, decenoic acid, decadienoic acid,lauroleic acid, laurolinoleic acid, myristovaccenic acid,myristolinoleic acid, myristolinolenic acid, palmitolinolenic acid,palmitidonic acid, α-linolenic acid, stearidonic acid,dihomo-α-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid,clupanodonic acid, docosahexaenoic acid,9,12,15,18,21-tetracosapentaenoic acid,6,9,12,15,18,21-tetracosahexaenoic acid, myristoleic acid,palmitovaccenic acid, α-eleostearic acid, β-eleostearic acid, punicicacid, 7,10,13-octadecatrienoic acid, 9,12,15-eicosatrienoic acid,β-eicosatetraenoic acid, 8-tetradecenoic acid, 12-octadecenoic acid,linoleic acid, linolelaidic acid, γ-linolenic acid, calendic acid,pinolenic acid, dihomo-linoleic acid, dihomo-γ-linolenic acid,arachidonic acid, adrenic acid, osbond acid, palmitoleic acid, vaccenicacid, rumenic acid, paullinic acid, 7,10,13-eicosatrienoic acid, oleicacid, elaidic acid, gondoic acid, erucic acid, nervonic acid,8,11-eicosadienoic acid, mead acid, sapienic acid, gadoleic acid,4-hexadecenoic acid, petroselinic acid, and 8-eicosenoic acid, or acombination of two or more thereof.

In another aspect of the disclosure for the compositions describedherein, the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system further comprises one or more polyacids,one or more water insoluble oligomers, one or more water insolublepolymers, or any combination thereof.

In a further aspect of the disclosure for the compositions describedherein, the polyacids can comprise, for example, a biocompatible fattypoly acid. In another aspect, the one or more polyacids can compriseglutaric acid (GA), poly(methacrylic acid-co-methyl methacrylate), orhypromellose phthalate (HPMC-P), or a combination of two or morethereof. In addition, the one or more polyacids can be present in thecomposition in an amount of about 1 wt. % to about 10 wt. %.

In another aspect of the disclosure for the compositions describedherein, the one or more water insoluble oligomers can comprise lowmolecular weight poly(hexyl substituted lactides) (PHLA), low molecularweight polyethylene, polyvinyl chloride, ethyl cellulose, or acrylatepolymers and copolymers thereof, or a combination of two or morethereof. In addition, the one or more water insoluble oligomers arepresent in the composition in an amount of about 1 wt. % to about 5 wt.%. Further, the one or more water insoluble polymers can comprise acopolymer of ethyl acrylate and methyl methacrylate,lactide-coglycolide, cellulose, or ethyl cellulose, or a combination oftwo or more thereof. Moreover, the one or more water insoluble polymerscan be present in the composition in an amount of about 1 wt. % to about5 wt. %.

In another aspect of the disclosure for the compositions describedherein, (a) the non-aqueous pH dependent release system is present in anamount between 10 wt. % and 95 wt. %; and (b) the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 90 wt. %.

In a further aspect of the disclosure for the compositions describedherein, (a) the non-aqueous pH dependent release system is present in anamount between 20 wt. % and 95 wt. %; and (b) the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 80 wt. %.

In yet another aspect of the disclosure for the compositions describedherein, (a) the non-aqueous pH dependent release system is present in anamount between 30 wt. % and 95 wt. %; and (b) the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 70 wt. %.

In one embodiment of the disclosure for the compositions describedherein, (a) the non-aqueous pH dependent release system is present in anamount between 40 wt. % and 95 wt. %; and (b) the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 60 wt. %.

In a further embodiment of the disclosure for the compositions describedherein, the non-aqueous pH dependent release system comprises: (a) atleast 15 wt. % of one or more monocarboxylic acids having at least 8carbon atoms, (b) at least 20 wt. % of one or more monocarboxylic acidshaving at least 8 carbon atoms, or (c) at least 30 wt. % of one or moremonocarboxylic acids having at least 8 carbon atoms.

In one aspect of the disclosure for the compositions described herein,the non-aqueous pH dependent release system comprises: (a) at least 15wt. % of a mixture of (i) one or more low melting point monocarboxylicacids, (ii) one or more medium melting point monocarboxylic acids, (iii)one or more high melting point monocarboxylic acids, or (iv) anycombination thereof, and (b) wherein: (i) the low melting pointmonocarboxylic acids have melting point temperatures less than or equalto room temperature, (ii) the medium melting point monocarboxylic acidshave melting point temperatures greater than room temperature and lessthan or equal to a body temperature of a mammal, or a human, and (iii)the high melting point monocarboxylic acids have melting pointtemperatures above the body temperature of a mammal, or a human.

In one embodiment of the disclosure for the compositions describedherein, the non-aqueous pH dependent release system further comprisesone or more neutral lipids. For example, the one or more neutral lipidscan comprise one or more biocompatible oils. In addition, the one ormore biocompatible oils can comprise peanut oil, canola oil, avocadooil, safflower oil, olive oil, corn oil, soybean oil, sesame oil,vitamin A, vitamin D, vitamin E, animal oils, fish oils, or krill oil,or a combination of two or more thereof. In another aspect, the one ormore neutral lipids can comprise a fatty acid ester. For example, thefatty acid ester can be a fatty acid methyl ester. Further, the fattyacid methyl ester can be methyl linolenate, methyl oleate, or methylpalmitate, or a combination of thereof. In a further aspect, the one ormore neutral lipids can be present in the composition in an amount ofabout 30 wt. % to about 75 wt. %.

In another embodiment of the disclosure for the compositions describedherein, the non-aqueous pH dependent release system further comprises(a) one or more low melting point neutral lipids; and/or (b) one or moremedium melting point neutral lipids; and/or (c) one or more high meltingpoint neutral lipids.

In a further embodiment of the disclosure for the compositions describedherein, the composition comprises less than 10 wt. % of one or moreselected from (1) fatty acid salts, (2) secondary complexing agents, (3)protective agents, (4) excipients, (5) adjuvants, (6) drying agents, (7)antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders.

In one aspect of the disclosure for the compositions described herein,the pharmaceutical composition comprises (a) a carrier compositionaccording to any one of claims 1 to 46; and (b) one or more biologicallyactive agents, wherein a weight ratio of the carrier composition to theone or more biologically active agents is between about 10:1 and about1:2. For this composition, the one or more biologically active agentscan be, for example, suspended in the carrier composition. Further, theone or more biologically active agents can be, for example, crystallinesolid particles. Additionally, the biologically active agent cancomprise at least one agent selected from the group consisting of anacid-labile pharmaceutical agent, an anti-depressant, an anti-diabeticagent, an anti-epileptic agent, an anti-fungal agent, an anti-malarialagent, an anti-muscarinic agent, an anti-neoplastic agent, animmunosuppressant, an anti-protozoal agent, an anti-tussive, aneuroleptics, a beta-blocker, a cardiac inotropic agent, acorticosteroid, an anti-parkinsonian agent, a gastrointestinal agent,histamine, a histamine receptor antagonist, a keratolytic, a lipidregulating agent, a muscle relaxant, a nitrate, an anti-anginal agent, anon-steroidal anti-inflammatory agent, a nutritional agent, an opioidanalgesic, a sex hormone, a stimulant, a nutraceutical, a peptide, aprotein, a therapeutic protein, a nucleoside, a nucleotide, DNA, RNA, aglycosaminoglycan, an acid-labile drug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amideranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole. In another aspect, the one or morebiologically active agents can be hydrophobic.

Further, the one or more biologically active agents can include an acidlabile drug. For example, the acid-labile drug can be selected from thegroup consisting of heparin, insulin, erythropoietin, pancreatin,lansoprazole, omeprazole, pantoprazole, rabeprazole, penicillin salts,benzathine penicillin, polymyxin, sulphanilamide, and erythromycin.

In another aspect, the one or more biologically active agents caninclude a non-steroidal anti-inflammatory agent (NSAID). For example,the NSAID can be selected from the group consisting of ibuprofen,piroxicam, salicylate, aspirin, naproxen, indomethacin, diclofenac,mefenamic acid, COX2 inhibitors, and any mixture thereof. In addition,the NSAID can be selected from the group consisting of aspirin,naproxen, indomethacin and mefenamic acid. Further, the NSAID can beaspirin.

Both the foregoing summary and the following description of the drawingsand detailed description are exemplary and explanatory. They areintended to provide further details of the invention, but are not to beconstrued as limiting. Other objects, advantages, and novel featureswill be readily apparent to those skilled in the art from the followingdetailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 illustrates the change for a high pH form (shown here as anemulsion comprising oil droplets in a high pH aqueous fluid or high pHenvironment) into a low pH form, shown here as an oil phase of amorphousstructures in the low pH aqueous fluid or low pH environment. In the topframe, the BAI concentration is shown higher in the higher pH aqueousphase (higher dot pattern shading) and lower in the oil droplets (lowerdot pattern shading). In the bottom frame, the BAI concentration isshown higher in the amorphous oil phase (higher dot pattern shading) andlower in the low pH fluid (lower dot pattern shading).

FIG. 2 illustrates matrix changes from the composition in its originalform as a solid-in-oil suspension to a micellar solution, which is theform the composition likely takes when the composition proceeds from thestomach to the duodenum. The composition then reforms into oil globulesdistributed in gastric fluid. The globules may coalesce into a singlecontinuous or into a semi-continuous phase. Again, the concentration ofBAI is shown by the dot pattern shading: lower dot pattern shading forlower BAI concentration and higher dot pattern shading for higher BAIconcentration. The BAI concentrations are likely controlled bypartitioning, but when the free fatty acids become deprotonated, thefree fatty acids are converted into anionic surfactants to stabilize themicelles.

FIG. 3 depicts photographs illustrating the mixing, the temperaturemonitoring, and the pH monitoring of a sample undergoing a pH cycle.

FIG. 4 depicts photographs of the control composition during a pH cyclesimulating simulate duodenal reflux: the left photograph shows thecontrol composition in the initial pH 1 solution (simulated gastricfluid), the middle photograph shows the control composition in the pH 7solution (simulated duodenal fluid) after concentrated NaOH addition tothe initial pH 1 solution, and the right photograph shows the controlcomposition in the final pH 1 solution (simulated gastric fluid) afterconcentrated HCl addition to the pH 7 solution.

FIG. 5 depicts photographs of the aspirin-containing composition duringa pH cycle simulating simulate duodenal reflux: the left photographshows the aspirin-containing composition in the initial pH 1 solution(simulated gastric fluid), the middle photograph shows theaspirin-containing composition in the pH 7 solution (simulated duodenalfluid) after concentrated NaOH addition to the initial pH 1 solution,and the right photograph shows the aspirin-containing composition in thefinal pH 1 solution (simulated gastric fluid) after concentrated HCladdition to the pH 7 solution.

FIG. 6 depicts photographs of the aspirin-containing composition duringtwo pH 7 adjustment cycles.

FIG. 7 depicts photographs comparing the control composition at pH 1 andthe aspirin-containing composition at different pH values.

FIG. 8 depicts a plot of UV aspirin (ASA) and salicylic acid (SA)concentration values of the aspirin-containing composition during a pHcycles, showing release, reconstitution and reabsorption of aspirin.

FIG. 9 depicts photographs of the ibuprofen-containing compositionduring a pH cycle.

FIG. 10 depicts photographs of the ibuprofen-containing compositionafter undergoing a pH cycle after sitting for one day (Day 1) and forfour additional days (Day 4).

FIG. 11 depicts a plot of UV ibuprofen concentration values for theibuprofen-containing composition during a pH cycle.

FIG. 12 depicts photographs of the preparation of theomeprazole-containing composition showing initial color and color changeupon addition of citric acid.

FIG. 13 depicts photographs of the omeprazole-containing compositionafter initial addition to the pH 1 solution, after pH adjustment, andafter sitting for a little while.

FIG. 14 depicts photographs of the omeprazole-containing composition inthe pH 1 solution during concentrated NaOH addition to adjust the pH topH 7.

FIG. 15 depicts photographs of the control composition, theomeprazole-containing composition, the omeprazole-containing compositionin the pH 1 solution, the omeprazole-containing composition in the pH 7solution, and the omeprazole-containing composition in the final pH 1solution.

FIG. 16 depicts a plot of UV omeprazole concentration values for theomeprazole-containing composition during a pH cycle.

FIG. 17 depicts a plot of a comparison of UV aspirin, ibuprofen, andomeprazole concentration values in the water phase during a pH cycle.

FIG. 18 depicts photographs of the high oleic acid-ibuprofen-containingcomposition during a pH cycle.

FIG. 19 depicts photographs of the control composition (no ibuprofen)and the high oleic acid-ibuprofen-containing composition after theconcentrated NaOH addition to adjust the pH to pH 7, showing that boththe control composition and the ibuprofen-containing composition formedvery stable emulsions at pH 7.

FIG. 20 depicts a plot of UV ibuprofen concentration values for the higholeic acid-ibuprofen-containing composition during a pH cycle.

FIG. 21 depicts photographs of the surfactant-ibuprofen-containingcomposition during a pH cycle.

FIG. 22 depicts a plot of UV ibuprofen concentration values for thesurfactant-ibuprofen-containing composition during a pH cycle.

FIG. 23 depicts a plot of comparing UV ibuprofen concentration valuesfor the ibuprofen-containing composition, the high oleicacid-ibuprofen-containing composition, andsurfactant-ibuprofen-containing composition during a pH cycle.

FIG. 24 depicts photographs of the control composition (no whey isolateprotein) and the whey isolate protein-containing composition duringpreparation.

FIG. 25 depicts photographs of a sample of the whey isolateprotein-containing composition in the initial pH 1 solution and in theNaOH adjusted pH 7 solution.

FIG. 26 depicts photographs of the sample of the whey isolateprotein-containing composition in all three solution of a pH cycle.

FIG. 27 depicts a plot of UV whey isolate protein percentage values forthe whey isolate protein-containing composition during a pH cycle.

FIG. 28 depicts a plot of a comparison of UV aspirin, ibuprofen, wheyisolate protein, and omeprazole percentage values for their respectivecompositions in the aqueous phase during a pH cycle.

FIG. 29 depicts photographs of a sample of the high acid (HA), nonionicsurfactant (NIS) whey isolate protein-containing composition in allthree solution during a pH cycle.

FIG. 30 depicts a plot of UV WIP percentage values for the HA, NIS wheyisolate protein-containing composition during a pH cycle.

FIG. 31 depicts a plot of a comparison of UV WIP percentage values forthe two whey isolate protein-containing compositions during a pH cycleevidencing a significant change in release and reabsorption propertiesof the oil matrix used for the proteins.

FIG. 32 depicts a plot of a comparison of UV API percentage values inthe aqueous phase for aspirin-, ibuprofen-, omeprazole-, and wheyisolate protein-containing compositions (with or without nonionicsurfactant) during a pH cycle.

FIG. 33 depicts photographs of the preparation of the nonionicsurfactant-aspirin-containing composition compared to the controlcomposition.

FIG. 34 depicts photographs of the nonionicsurfactant-aspirin-containing composition during a pH cycle.

FIG. 35 depicts a plot of UV aspirin concentration values for theNIS-ASA-containing composition during a pH cycle.

FIG. 36 depicts a plot comparison of UV aspirin concentration values forthe two aspirin-containing compositions (with or without nonionicsurfactant) during a pH cycle.

FIG. 37 depicts a plot of a comparison of UV API percentage values inthe aqueous phase for aspirin-, ibuprofen-, omeprazole-, and wheyisolate protein-containing compositions (with or without nonionicsurfactant) during a pH cycle.

DETAILED DESCRIPTION OF THE DISCLOSURE I. Overview

Certain embodiments of the present disclosure relate to systems andcompositions including a nonaqueous carrier and one or more biologicallyactive agents (BAIs) to form a tailored biologically active agentrelease non-aqueous matrix having improved GI protection due to duodenalreflux and to methods for making and using same.

A. Reassembling Drug Carriers

The carriers of this disclosure include one or more non-aqueous targetedrelease agents and one or more non-aqueous reconstitutive agents to formunique non-aqueous matrices for targeted release of one or morebiologically active agents (BAIs) and targeted matrix reassembly ortargeted matrix assembly. The reassembled matrix or newly assembledmatrix are capable of absorbing BAIs via partitioning. The carriers areformulated to: (a) have a first form or low pH form in low pHenvironments such as aqueous fluids having a pH less than or equal toabout pH 3 (≤about pH 3), (b) have a second form or high pH form in highpH environment such as aqueous fluids having a pH greater than about pH3 (>pH 3), and (c) reassemble into the low pH form or assemble into anew low pH form after passing from a low pH environment to a high pHenvironment and back to a low pH environment such as passing through thestomach into the duodenum and back into the stomach due to duodenalreflux. In certain embodiments, the carriers may also include one ormore neutral lipids.

Additionally, the carriers disclosed herein are designed to: (a)minimally release one or more biologically active agents from their lowpH form in contact with low pH aqueous fluids; (b) maximally release oneor more BAIs from their high pH form providing pH dependent targetedrelease of BAIs within tracts having different pH environments along thelength of the tracts; and (c) absorb any BAI into their reassembled lowpH form or their newly assembled low pH form to reduce injury orirritation to the low pH environment or to reduce decomposition of anyBAI reentering the low pH environment from the high pH environment suchas any biologically active agent present in duodenal reflux.

Thus, the carriers are capable of being formulated to target release ofBAIs based on pH into a tissue tract having a pH profile across thelength of the tract such as the gastrointestinal (GI) tract, urinarytract, reproductive tract, or other tracts that have mucosal gels anddiffer in pH along the tract. Carrier-mediated targeted release isparticularly useful for: (a) BAIs injurious to certain portions of thetracts such as the esophagus or the stomach, (b) acid labile BAIs, e.g.,BAIs that decompose or are destroyed in low pH or acidic environmentssuch as gastric fluid, (c) biologically active agents that areimpermeable/insoluble in low pH fluids, e.g., gastric fluid, (d) BAIssusceptible to first pass metabolism, and/or (e) BAIs that cause stomachulceration, irritation, upset, or dyspepsia.

In certain embodiments, the targeted release carriers include one ormore pH dependent release agents include at least one ionizable groupsuch as a carboxylic acid group (—COOH), hydroxy group (—OH), thiolgroup (—SH), sulphonic acid group (—SO₃H), sulphonamide group (—SO₂NH₂),imide group (—C(O)NHC(O)R), amide group (—C(O)NHR), amine salt(—NR₂H⁺X⁻), etc. and/or protonatable group such as amino group (e.g.,—NH₂, —NHR, or —NR₂), amide group (—C(O)NHR), imide group(—C(O)NHC(O)R), etc., wherein each of the R groups are hydrocarbylgroups. In certain embodiments, the release agents include one or morecarboxylic acid groups. In other embodiments, the release agents includeone or more oil soluble or oil miscible compounds including at least onecarboxylic acid group.

In other embodiments, the pH dependent, oil soluble or oil misciblerelease agents include one or more fatty acids sometimes referred toherein as free fatty acids. The term free fatty acids (FFAs) refer tocarboxylic acids having a hydrocarbon tail of generally formula R—COOH,wherein R is a hydrocarbon or hydrocarbyl group generally having atleast 8 carbon atoms, sometimes between 8 and 40 carbon atoms. FFAs areto be distinguished from compounds that include fatty acids as a moietyin their molecular structure such as mono-glyceride, di-glycerides,tri-glycerides, or fatty acid esters such as methyl, ethyl, propyl, etc.esters of the general formula R—COOR′, where R and R′ are hydrocarbon orhydrocarbyl groups.

In certain embodiments, the one or more non-aqueous reconstitutiveagents include, without limitation, (a) neutral lipids, (b) surfactantssuch as non-ionic surfactants, anionic surfactants, cationicsurfactants, and/or zwitterionic surfactants, (c) compounds, oligomers,polymers, or copolymer including carboxylic acid moieties, and/or (d)any other component that stabilizes oil matrices or assists in matrixformation. Such matrices are capable of absorbing BAIs from low pHfluids due to partitioning. The absorption of BAIs from low pH fluidswould reduce injury and/or irritation to low pH environment tissues dueto the BAIs and/or would reduce decomposition or destruction of BAIs inlow pH environments or low pH aqueous fluids. For example, the one ormore non-aqueous reconstitutive agents are designed to assist in thereformation of the low pH matrix or formation of a new low pH matrix dueto duodenal reflux, where the reformed low pH matrix and/or the newlyformed low pH matrix absorb BAIs. In certain embodiments, the carriersmay be taken without a BAI to absorb BAIs known to be injurious to thestomach (GI toxicity) or known to be destroyed or decompose in thestomach, especially BAIs that are injurious and persistent such asnaproxen.

B. Compositions Including Targeted Release and Reconstitutive/AbsorptiveCarriers

Some embodiments of the present disclosure provide compositionsincluding a carrier of this disclosure and a therapeutically effectiveamount one or more BAIs, wherein the carrier is designed to effect atargeted release of the BAIs and/or to modify and/or alter the chemicalproperties, physical properties, and/or behavior of the BAIs in tissuesand/or organs, when administered to an animal, mammal, or human. Thecarrier is also designed to facilitate reconstitution back into its lowpH carrier structure or form, or newly form a low pH carrier structureor form due to duodenal reflux: the carrier transitions from its high pHform back into its low pH form(s) when changing from a high pHenvironment back into a low pH environment.

In certain embodiments, the compositions include a carrier of thisdisclosure and a therapeutically effective amount of one or morepharmaceutical active ingredients (APIs) and/or one or morenutraceutical agents, wherein the carrier is designed to effect atargeted release of the APIs and/or nutraceutical agents and/or tomodify and/or alter the chemical properties, physical properties, and/orbehavior of the agents in tissues and/or organs of the APIs ornutraceuticals, when administered to an animal, mammal, or human and tofacilitate matrix reconstitution due to duodenal reflux.

The above compositions may be in the form of a solution of the BAIs inthe carrier, a suspension of solid BAIs in the carrier, wherein some ofthe BAIs may be dissolved in the carrier, a suspension of the BAIs inthe carrier, wherein no active agent is dissolved in the carrier, apaste of the BAIs in the carriers, or any other mixture or combinationof the BAIs in the carriers or surrounded by the carriers. The BAIs maybe present in the carrier in an amount sufficient to produce asolid-in-oil suspension, a paste like suspension, a coated solidmaterial such as coated crystals or coated micro- or nano-particles,where the coating may be from a monolayer to millimeters in thickness, amatrix of coated solid material, or any other form including a carrierof this disclosure and one or more active agents.

In some embodiments, the present disclosure broadly relates topharmaceutical compositions comprising (1) a carrier comprising: (a) anon-aqueous pH dependent release system; and (b) a non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system,wherein the carrier composition has a low pH form and a high pH form,wherein the carrier composition is formulated to release one or morebiologically active agents minimally from its low pH form and maximallyor at a higher level from its high pH form due to the non-aqueous pHdependent release system, wherein the carrier composition is formulatedto either reassembly into its low pH form and/or assembly into a new lowpH form due to the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system, and wherein the carrier is formulated toeither reabsorb the one or more biologically active agents in itsreassembled form and/or absorb the one or more biologically activeagents in its newly assembly form, and (2) one or more biologicallyactive agents, wherein a weight ratio of the carrier to the one or morebiologically active agents is between about 10:1 and about 1:2.

In certain embodiments, the non-aqueous pH dependent release system ispresent in an amount between 10 wt. % and 95 wt. %; and the non-aqueouspH dependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 90 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 20 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 80 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 30 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 70 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 40 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 60 wt. %. In otherembodiments, the non-aqueous pH dependent release system comprises: atleast 15 wt. % of one or more monocarboxylic acids having at least 8carbon atoms, at least 20 wt. % of one or more monocarboxylic acidshaving at least 8 carbon atoms, or at least 30 wt. % of one or moremonocarboxylic acids having at least 8 carbon atoms.

In other embodiments, the non-aqueous pH dependent release systemcomprises at least 15 wt. % of a mixture of (a) one or more low meltingpoint monocarboxylic acids, (b) one or more medium melting pointmonocarboxylic acids, (c) one or more high melting point monocarboxylicacids, or (d) any combination thereof, wherein the low melting pointmonocarboxylic acids have melting point temperatures less than or equalto room temperature, wherein the medium melting point monocarboxylicacids have melting point temperatures greater than room temperature andless than or equal to a body temperature of an animal, a mammal, or ahuman, and wherein the high melting point monocarboxylic acids havemelting point temperatures above the body temperature of an animal, amammal, or a human. In other embodiments, the non-aqueous pH dependentrelease system further comprises one or more neutral lipids. In otherembodiments, the non-aqueous pH dependent release system furthercomprises: a mixture of (a) one or more low melting point neutrallipids, (b) one or more medium melting point neutral lipids, (c) one ormore high melting point neutral lipids, or (d) any combination thereof,wherein the at low melting point neutral lipids have melting pointtemperatures less than or equal to room temperature, wherein the mediummelting point neutral lipids have melting point temperatures greaterthan room temperature and less than or equal to a body temperature of ananimal, a mammal, or a human, and wherein the high melting point neutrallipids have melting point temperatures greater than the body temperatureof an animal, a mammal, or a human.

In other embodiments, the non-aqueous pH dependent reassembly/assemblyand reabsorption/absorption system comprises: (a) one or more polyacids,(b) one or more polymers including a plurality of carboxylic acidmoieties, (c) one or more surfactants, (d) one or more water insolubleoligomers, (e) one or more water insoluble polymers, or (f) anycombination thereof. In other embodiments, the pharmaceuticalcompositions further comprise: less than 10 wt. % of one or moreselected from (1) fatty acid salts, (2) secondary complexing agents, (3)protective agents, (4) excipients, (5) adjuvants, (6) drying agents, (7)antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders.

C. Methods for Making

Some embodiments of the present disclosure provide methods for makingthe carriers of this disclosure by contacting components together underconditions of mixing, temperature, pressure, and time sufficient to forma carrier having engineered BAI release, reconstitutive, and BAIabsorptive properties. In certain embodiments, a solvent system may beused, but the solvent must be removed so that the carriers aresubstantially free solvent. The removal process may be distillation,evaporation, vacuum distillation, vacuum evaporation, any other solventremoval techniques, or any combination thereof.

Some embodiments of the present disclosure provide methods for makingthe compositions by contacting or admixing a therapeutically effectiveamount of one or more BAIs into a carrier of this disclosure underconditions of mixing, temperature, pressure, and time sufficient to forma composition, wherein the carrier is a liquid at biologicaltemperatures and the carrier is engineered so that the BAIs are releasedin a pH dependent nature and the carrier is engineered to reconstitutecapable of absorbing BAIs due to partitioning between an aqueous fluidand the non-aqueous matrix. In certain embodiments, the BAIs are simplyadmixed into the carrier under conditions of mixing, temperature,pressure, and time sufficient to form a composition for this disclosure.

In certain embodiments, the BAIs comprise one or more APIs and/or one ormore nutraceutical agents.

It should be recognized by an ordinary artisan that the admixing methodreduces step and eliminates any concern for solvent removal or tracesolvent contamination allowing for lower manufacturing cost,environmental manufacturing concerns, etc. Alternatively, certainformulations may benefit from solvation of the ingredients. In certainembodiments, the APIs and/or nutraceutical agents are solids and theadmixing method simply involves mixing the solid APIs and/or solidnutraceutical agents into the carrier to form solid-in-oil suspension orpaste, i.e., a suspension of the solid APIs and/or solid nutraceuticalagents in an oil matrix. In other embodiments, the APIs and/ornutraceutical agents are liquids and the admixing method simply involvesmixing the liquid APIs and/or liquid nutraceutical agents into thecarrier to form an oil matrix including the liquid APIs and/or liquidnutraceutical agents. In other embodiments, the APIs and/ornutraceutical agents are a mixture of solids and liquids. Again, if asolvent system is used, the solvent is removed so that the compositionsare substantially free of solvent, wherein the removal techniques may bedistillation, evaporation, vacuum distillation, vacuum evaporation, anyother solvent removal technique, or any combination thereof.

Some embodiments of the present disclosure provide methods includingadministering an effective amount of a composition of this disclosure toa human, mammal, or animal, wherein the effective amount of thecomposition results in a therapeutically effective amount of the one ormore BAIs such as APIs and/or one or more nutraceutical agentssufficient to illicit a desired response. The mode of administration maybe oral administration, sublingual or rectal administration, oresophageal, gastric, intestinal instillation via endoscopy. In certainembodiments, the administration may be topical such as administrationinto ophthalmic, urinary, the reproductive, or other tract, tissue, ororgan for which topical administration represents an effective treatmentmethodology. In other embodiments, the administration may be parenteral.

D. Further Characteristics of the Compositions and Carriers

More particularly, some embodiments of the present disclosure relate tosystems and compositions including a non-aqueous carrier and one or morebiologically active agents (BAIs) to form a tailored biologically activeagent release non-aqueous matrix having improved GI protection due toduodenal reflux and to methods for making and using same. The carriers:(a) have a first or low pH form, wherein the low pH form issubstantially insoluble in fluids having a pH less than or equal toabout pH 3 and releases minimal amounts of the one or more biologicallyactive agents in the low pH fluids, (b) have a second or high pH form,wherein the high pH form changes in fluids having a pH greater the pH 3and releases substantial amounts of the one or more biologically activeagents in the high pH fluids, (c) reassemble into the low pH form and/orassemble into a new low pH form after passing through the stomach intothe duodenum and back into the stomach due to duodenal reflux, and (d)the reassembled low pH form and/or assembled new low pH form absorbs aportion of any biologically active agent present in the duodenal refluxto reduce stomach injury or irritation or to reduce the loss of anybiologically active agent present in the duodenal reflux. In certainembodiments, the carriers may be administered to absorb a portion of oneor more biologically active agents due to duodenal reflux, wherein theone or more biologically active agents are known gastric irritants, haveknown gastric stomach toxicity, have long therapeutic lifetimes, or aredestroyed or decompose in the stomach.

Drug delivery systems have been studied for years. PLx Pharma Inc. hasbeen instrumental in advancing the art of drug delivery systems bydiscovering that carriers may be designed that deliver biologicallyactive agents to different parts of the GI tract based solely on pH.These carriers were based on using a sufficient amount of free fattyacid (long chained carboxylic acids), where the pH dependent behavior ofthe free fatty acid were thought to be based on the fact that at low pHvalues below about pH 3, the free fatty acids or carboxylic acids existin their protonated form (R—COOH, where R is a hydrocarbyl group) and athigh pH values above pH 3, especially a pH above the pKa of the freefatty acid, the free fatty acids or carboxylic acids exit in theirionized or deprotonated form as a salt (R—COO⁻A⁺, where R is as aboveand A⁺ is a counterion like Na⁺, K⁺, Ca₂ ⁺, NH₄ ⁺, etc.) and act assurfactants.

Another class of drug delivery systems that release biologically activeagents outside of the stomach are biologically active agents coated withpolymers that breakdown in high pH environments or by the active ofcertain enzymes present in high pH environments of the GI tract. Thesepolymeric coatings are not liquids and PLx Pharma has shown that aspirinreleased from such polymer-coated compositions is very slow and oftenunpredictable. Thus, so-called enteric coated aspirin are incapable ofquickly releasing aspirin for patients that may be in immediate need ofthe anti-platelet activity of aspirin.

While there are compositions that show pH dependent release ofbiologically active agents, there is still a need in the art for new andnovel pharmaceutical carriers and compositions based on the carriersthat are capable of not only targeted release of biologically activeagents, but are also capable of reconstitution and reabsorption of thebiologically active agents upon back flow into the stomach to protectthe stomach from injury from the biologically active agents or toprotect the biologically active agents from further loss due todegradation in the stomach.

The present inventors have found that unique compositions may beprepared for pH dependent release of one or more biologically activeagents (BAIs) including active pharmaceutical ingredients (APIs) and/ornutraceutical agents and for pH dependent reconstitution and absorptionof BAIs, when the compositions transitions from a low pH environment, toa high pH environment and back to a low pH environment such as occurs induodenal reflux. The inventors have found that pH dependent release ofBAIs, pH dependent carrier assembly or reassembly, and BAI absorption orreabsorption is controlled by the nature of the carrier used in thecompositions. The carriers are oil based, generally essentially free ofwater and/or solvents, and control the targeted release of BAIs intracts in an animal, mammal, or human that have different pH valuesalong a length of the tract such as the gastrointestinal (GI) tract, theurinary tract, the reproductive tract, or tissues such as ophthalmictissue. Because the carriers are oil based and include pH dependentrelease agents, the carriers are also designed to assembly or reassemblywhen the carrier transitions from a high pH environment back to a low pHenvironment. Further, the assembled and/or reassembled carriers aredesigned to absorb and/or reabsorb BAIs in the low pH environments. Thecarriers of this disclosure are formulated to reduce injury to thestomach mucosa during initial passage through the stomach into theduodenum for BAIs known to be injurious or irritants to the stomachmucosa and to reduce injury due to duodenal reflux or to reduce loss ofbiologically active agents that decompose or are destroyed in gastricfluid.

1. NSAIDs

For example, non-steroidal anti-inflammatory drugs (NSAIDs) are known tocause significant gastrointestinal (GI) toxicity. This issue isparticularly relevant to aspirin that in contrast to the other NSAIDs isindicated as a lifelong therapy for patients with cardiovasculardisease. The GI symptoms from chronic aspirin use range from bloatingand dyspepsia all the way to life threatening bleeding as a result ofulcer formation. The majority of the toxic side effects due to the useof aspirin includes the appearance of erosions or ulcers in the stomach.Other NSAIDs are also known to have the same or similar toxic effects onthe stomach.

The ability, therefore, to deliver an NSAID past the stomach and intothe duodenum instead is a logical approach to limit toxicity. Onetechnique for accomplishing this delayed release is to utilize entericcoat tablets with that goal in mind and employ a pH-dependent coatingdecomposition to delay the release of the NSAID until the compositionpasses out of the stomach, a low pH environment, into the smallintestines, a high pH environment. Accordingly, the polymer coatingremains intact and only begins degrading and allowing the componentNSAID, especially aspirin, to be released once the pH rises above pH 7in the small intestines, a pH and environment necessary for the entericcoating degradation. Once released, the aspirin is free standing in theGI tract and available for absorption.

The degradation of enteric coatings is associated with significantinter- and intra-patient variability and results in unpredictable ratesof aspirin release and absorption. More importantly, the promise ofimproved GI safety has not been fulfilled in clinical practice andstudies have demonstrated that the risk of aspirin-induced GI bleedingis the same with enteric-coated aspirin formulations as compared toregular, immediate release aspirin formulations that deliver aspirin inthe stomach. It appears therefore that the unidirectional, one-passprotection provided by the enteric polymer coating is insufficient tolimit toxicity to the stomach.

The explanation for this observation relates to the normal digestiveprocess that relies on continuous mixing of the luminal contents throughongoing peristalses. Accordingly, contents routinely reflux back intothe stomach from the duodenum to allow for better mixing and digestion.Therefore, once the enteric-coated tablet arrives in the higher pH ofthe duodenum, it loses the polymer protection and releases the aspirin,which is then free to reflux back into the stomach and cause injury.

The NSAID compositions of this disclosure also employ a pH dependentrelease mechanism; however, rather than a polymer coating, the presentcompositions rely on the chemical nature of the carriers of thisdisclosure in which the NSAIDs are suspended, where the carriersminimally release the NSAIDs, or other biologically active agents, inlow pH environments and efficiently or maximally release the NSAIDs orrelease the NSAIDs at a higher level, or other biologically activeagents, in high pH environments.

Clinical studies have shown that aspirin absorption from compositions ofthis disclosure is both complete and reliable and in fact isbioequivalent to immediate release aspirin formulations. However, thereis an additional very important differentiation of the compositions ofthis disclosure and it relates to the dynamic nature of the chemicalnature of the carrier and its interaction with the solid NSAIDs, e.g.,aspirin, or any other solid biologically active agent. Specifically, thecarriers of this disclosure have been engineered both to releasebiologically active agents such as NSAIDs in a pH dependent manner andto reassemble or reconstitute when the carrier transitions from a highpH environment back into a low pH environment due to duodenal reflux.The reassembled or reconstituted carriers are then capable ofreabsorbing any biologically active agents also refluxed back into thestomach from the duodenum. Accordingly, the protection from injury ismaintained during the full digestive process compared with the one-passprotection from enteric coated tablets or other pH dependent carriersthat only affect a pH dependent release, but not protection due toduodenal reflux. This differentiation in the mechanism of action of theengineered carriers of this disclosure is of very high clinicalrelevance since it allows for bidirectional stomach protection for thefirst time ever. This improved stomach protection not only lowers therisk for serious complications such ulcers or even life threateningbleeding, but the improved protection also reduces the dyspeptic burdenthat frequently leads patients to discontinue this life saving therapy.

2. Acid Labile Biologically Active Agents

For compositions including acid labile biologically active agents orAPIs, the reconstitution not only reduces the amount of API refluxedback into the stomach from causing stomach toxicity, but also reducesthe loss of the API due to degradation in the stomach.

Thus, the inventors have found that by a very careful engineering of thecarriers of this disclosure not only may the carriers affect a pHdependent release of the biologically active agents, but may alsoreconstitute during duodenal reflux affecting a reabsorption of thebiologically active agents. The ability for the engineered carrier toreassemble or reconstitute, may also allow for the formulation ofcompositions that may be taken during administration of biologicallyactive agents known to efficiently reflux from the duodenum back intothe stomach such as naproxen or other persistent biologically activeagents known to be injurious to the stomach. The ability of theengineered carrier to reassemble or reconstitute also further reducesany decomposition of acid labile biologically active agents.

As the population of the world and particularly the United States hasincreasing numbers of older citizens and citizens that are physicallyheavier than previous generations, the need for new delivery systems forbiologically active agents or APIs that mitigate against certain adverseeffects such as adverse GI affects increases, especially fornon-steroidal, anti-inflammatory drugs (NSAIDs). NSAIDs are ubiquitouslyused drugs for managing pain, for reducing or managing cardiovasculardisease, for reducing platelet aggregation, for reducing fever, forreducing or preventing cancer, and for a number of other uses. However,NSAIDs have a major drawback; they all have, to some extent, the abilityto cause irritation, erosion, and/or ulceration of the stomach and upperGI tract.

Previous work showed that fatty acids were capable of controlling therelease of biologically active agents in a pH dependent manner as setfor in U.S. Pat. Nos. 10,179,104; 9,730,884; 9,226,892; and 9,216,150,each incorporated by reference herein in their entirety. However, no onerecognized that such compositions could be designed to facilitatecomposition reconstitution and reabsorption biologically active agentsdue to duodenal reflux. It is believed that thisreconstitution/reabsorption results in further reduction of possiblestomach mucosa lining damage, irritation, or injury or further reductionin the loss of biologically active agents in low pH environment,especially for biologically active agents that decomposes or aredestroyed in low pH environments.

II. Pharmaceutical Carrier Compositions

It was found that the compositions including one or more biologicallyactive agents and a targeted release or pH dependent release carrier,which includes at least one compound that undergoes a change in at leastone chemical property in a pH dependent manner such as undergoingprotonation or deprotonation, may be further formulated to include atleast one compound capable of pH dependent carrier reassembly or carrierassembly during duodenal reflux, wherein the reassembled or newlyassembled carrier is capable of absorption or reabsorption of the one ormore biologically active agents.

In some embodiments, the carriers of the present disclosure are designedto form hydrophobic matrices in which an active agent is mixed as asolid or liquid (depending on the nature of the active agent). Thesehydrophobic matrices operate to modify, alter, change, or augmentchemical and/or physical characteristics of the active agent byproviding an immiscible/different environment compared to an aqueousbiofluid such as blood, gastric fluids, duodenal fluids, smallintestinal fluids, large intestinal fluids, vaginal fluids, rectalsolids/fluids, or any other biofluid setting up a situation where theactive agent is free to partition between the two immiscibleenvironments. Additionally, properties of the carriers of thisdisclosure such as viscosity, lipophilicity, hydrophobicity,dispersibility, dispensability, softening temperature, meltingtemperature, etc. also act to modify, alter, change, or augment the rateof partitioning of the active agent by sequestering the active agent inthe immiscible carrier until the carrier matrix is dispersed to smallenough particles to facilitate mass transfer from the immiscible carrierinto the appropriate biofluid. For solid active agents sequestered in acarrier matrix of this disclosure, an added reduction in partitioningrate ensues because the active agent must migrate out of the matrix anddissolve as the particle size of the matrix reduces in the biofluid dueto mechanic actions of the tissue and/or organ and/or due to biochemicalprocesses occurring in the tissue and/or organ.

In some embodiments, the present disclosure broadly relates tocompositions comprising: (1) a carrier as disclosed herein, and (2) atleast one biologically active agent. The carrier includes an effectiveamount of a pH dependent release system sufficient for a targetedrelease of the biologically active agents at a desired pH and aneffective amount of a carrier reassembly/assembly and biologicallyactive agent reabsorption/absorption system sufficient to reassemble thecarrier to its low pH form or assemble a new low pH carrier in low pHenvironments and to reabsorb or absorb the biologically active agentscontained in the original carrier.

Generally, the pH dependent release systems cause the at least onebiologically active agent to be released in a pH sensitive mannercharacterized in that less than 20% of the at least one biologicallyactive agent is released into gastric fluid and greater than 50% of theat least one biologically active agent is released in an intestinalfluid such as duodenum fluid. In other embodiments, the carriersefficiently release the at least one biologically active agent in highpH environments and reassemble and reabsorption or assembly and absorbthe at least one biologically active agent due to a transition from ahigh pH environment to a low pH environment as a result of duodenalreflux. In other embodiments, the carriers release the biologicallyactive agents minimally at a first pH and efficiently at second pH andreconstitute and reabsorb or assembly and absorb the at least onebiologically active agent at the first pH due to duodenal reflux. Inother embodiments, the carriers release the biologically active agentsminimally in the stomach and efficiently in the duodenum andreconstitute and reabsorb or form a new carrier and absorb the at leastone biologically active agent in the stomach due to duodenal reflux.

In other embodiments, the present disclosure relates broadly topharmaceutical compositions comprising a carrier and at leastpharmaceutically active ingredient (API) such as one weak acidnon-steroidal anti-inflammatory drug (NSAID). The carrier includes aneffective amount of a pH dependent release system sufficient for atargeted release of the API at a desired pH and an effective amount of areassembly/assembly and reabsorption/absorption system sufficient toreassemble the carrier into its low pH form or to form a new low pHcarrier due to duodenal reflux with concurrent reabsorption orabsorption of the API. Generally, the carrier releases the API in a pHsensitive manner characterized in that less than 20% of the API isreleased into gastric fluid and greater than 50% of the API is releasedin intestinal fluid having a pH value greater than pH 3 andreconstitutes and reabsorbs the API in gastric fluid or form a new lowpH carrier that absorbs the API. In other embodiments, the compositionsfurther include at least one secondary agent for the biologically activeagents, which generally reduce the toxicity or reduce the acid inducedhydrolysis of the biologically active agents. In other embodiments, thecompositions of this disclosure are non-aqueous including only residualwater and are immiscible in water or aqueous solutions, but are capableof being dispersed in aqueous solutions releasing the biologicallyactive agent in a pH dependent manner. In other embodiments, thecarriers of this disclosure are oil-based including only residual waterand are immiscible in water or aqueous solutions, but the carriers arecapable of being dispersed in aqueous solutions releasing the BAI orBAIs.

In other embodiments, the carriers of this disclosure may be tailored tohave good targeted active agent release characteristics, to have reducedactive agent toxicity or irritation, to have increased active agentbioavailability, and to have increased active agent migration acrossrelatively hydrophobic barriers in a human, mammal or animal. In otherembodiments, the carriers of this disclosure may be tailored to havegood targeted active agent release characteristics, to have reducedactive agent GI toxicity or irritation, to have increased active agentbioavailability, and to have increased active agent migration acrossrelatively hydrophobic barriers in a human, mammal or animal.

Some embodiments of the present disclosure relate to compositionscomprising a carrier including an effective amount of a least onetargeted release agent and an effective amount of at least onereassembly/assembly and reabsorption/absorption agent and atherapeutically effective amount of at least one biologically activeagent, where the carrier composition and/or its components are capableof controllably releasing the at least one biologically active agentinto certain portions of the gastro-intestinal (GI) tract andcontrollable reassembly/assembly and reabsorption/absorption of the atleast one biologically active agent due to duodenal reflux. In otherembodiments, the carrier and/or its components modify and/or alter thechemical and/or physical properties and/or behavior of the at least oneactive agent in tissues and/or organs reducing and/or altering tissueand/or organ toxicity, improving and/or altering bioavailability, and/orimproving and/or altering efficacy. In other embodiments, the carriersare capable of releasing the at least one BAI in a pH dependent manner.In other embodiments, the biocompatible targeted release agents compriseat least one biocompatible free fatty acid having at least 8 carbonatoms.

Some embodiments of the present disclosure relate to a compositioncomprising a carrier including up to 80 wt. % of one or more free fattyacids, up to 40 wt. % of one or more surfactants and up to 50 wt. % ofone or more neutral lipids, where the weight percentages of allcomponents in the composition add up to 100 wt. %, and an effectiveamount of at least one biologically active agent, where the carriercomposition and/or its components are capable of controllably releasingat least one active agent into certain portions of the gastro-intestinal(GI) tract. In other embodiments, the carrier and/or its componentsmodify and/or alter the chemical and/or physical properties and/orbehavior of the at least one active agent in tissues and/or organsreducing and/or altering tissue and/or organ toxicity, improving and/oraltering bioavailability, and/or improving and/or altering efficacy. Insome embodiments, the one or more surfactants include a mixture ofnonionic surfactants. In some embodiments, the one or more surfactantsinclude a mixture of nonionic surfactants, cationic surfactants, andzwitterionic surfactants in a weight ratio of nonionic surfactants tocationic and zwitterionic surfactants between about 50:1 and 1:1. Insome embodiments, the one or more surfactants include a mixture ofnonionic surfactants, anionic surfactants, and zwitterionic surfactantsin a weight ratio of nonionic surfactants to anionic and zwitterionicsurfactants between about 50:1 and 1:1. In some embodiments, the one ormore surfactants include a mixture of nonionic surfactants and cationicsurfactants in a weight ratio of nonionic surfactants to cationicsurfactants between about 50:1 and 1:1. In some embodiments, the one ormore surfactants include nonionic surfactants and anionic surfactants ina weight ratio of nonionic surfactants to anionic surfactants betweenabout 50:1 and 1:1. In some embodiments, the surfactants include amixture of nonionic surfactants and zwitterionic surfactants is a weightratio of nonionic surfactants to zwitterionic surfactants between about50:1 and 1:1.

Some embodiments of the present disclosure relate to a compositioncomprising a carrier including greater than about 15 wt. % of at leastone biocompatible free fatty acid having at least 8 carbon atoms,greater than about 20 wt. % of at least one biocompatible free fattyacid having at least 8 carbon atoms, or greater than about 30 wt. % ofat least on biocompatible free fatty acid; greater than about 10 wt. %of a mixture of surfactants, greater than about 20 wt. % of a mixture ofsurfactants, or greater than about 30 wt. % of a mixture of surfactants;and a remainder comprising at least one neutral lipid, where the freefatty acids, the surfactants, and the neutral lipids are immiscible inwater, where the weight percentages of all components in the compositionadd up to 100 wt. %, and an effective amount of at least onebiologically active agent, where the carrier composition and/or itscomponents are capable of controllably releasing at least one activeagent into certain portions of the gastro-intestinal (GI) tract. Inother embodiments, the carrier and/or its components modify and/or alterthe chemical and/or physical properties and/or behavior of the at leastone active agent in tissues and/or organs reducing and/or alteringtissue and/or organ toxicity, improving and/or altering bioavailability,and/or improving and/or altering efficacy. In other embodiments, themixture of surfactants comprises at least one nonionic surfactant and atleast one zwitterionic surfactant is a weight ratio of the at least onenonionic surfactant to the at least one zwitterionic surfactants betweenabout 50:1 and 1:1.

In other embodiments, the present disclosure relates broadly topharmaceutical compositions including a carrier of this disclosure andan effective amount of a pharmaceutical agent or a mixture ofpharmaceutical agents to form a solution and/or a suspension of thepharmaceutical agent or the mixture of pharmaceutical agents in thecarrier. In certain embodiments, the pharmaceutical compositions may betailored to have good targeted pharmaceutical release characteristics,to have reduced pharmaceutical toxicity or irritation, to have increasedpharmaceutical bioavailability, and to have increased pharmaceuticalmigration across relatively hydrophobic barriers in a human, mammal oranimal. In other embodiments, the pharmaceutical compositions may betailored to have good targeted pharmaceutical release characteristics,to have reduced pharmaceuticals GI toxicity or irritation, to haveincreased pharmaceutical bioavailability, and to have increasedpharmaceutical migration across relatively hydrophobic barriers in ahuman, mammal or animal.

In other embodiments, the present disclosure relates broadly tonutraceutical compositions including a carrier of this disclosure and aneffective amount of a nutraceutical agent or a mixture of nutraceuticalagents to form a solution and/or a suspension of the nutraceutical agentor a mixture of nutraceutical agents in the carrier. In certainembodiments, the nutraceutical compositions may be tailored to have goodtargeted nutraceutical release characteristics, to have reducednutraceutical toxicity or irritation, to have increased nutraceuticalbioavailability, and to have increased nutraceutical migration acrossrelatively hydrophobic barriers in a human, mammal or animal. In otherembodiments, the nutraceutical compositions may be tailored to have goodtargeted nutraceutical release characteristics, to have reducednutraceutical GI toxicity or irritation, to have increased nutraceuticalbioavailability, and to have increased nutraceutical migration acrossrelatively hydrophobic barriers in a human, mammal or animal.

In other embodiments, the pharmaceutical agent is an NSAID. In otherembodiments, the NSAID compositions of this disclosure may also include:(1) a pharmaceutically acceptable amount of antioxidant selected fromthe group consisting of Vitamin A, Vitamin C, Vitamin E or otherantioxidants approved for a human, mammal or animal consumption by theFDA and mixtures or combinations thereof; (2) a pharmaceuticallyacceptable amount of a polyvalent cation selected from the groupconsisting of copper, zinc, gold, aluminum and calcium and mixtures orcombinations thereof; (3) a pharmaceutically acceptable amount of anagent to promote fluidity, enhance viscosity, promote spreadability,promote dispersibility and/or promote permeability selected from thegroup consisting of dimethylsulfoxide (DMSO), propylene glycol (PPG),and medium chain triglyceride/MCT and mixtures or combination thereof;(4) a pharmaceutically acceptable amount of a food coloration ornon-toxic dye; (5) a pharmaceutically acceptable amount of a flavorenhancer; (6) an excipient; and/or (7) an adjuvant.

In other embodiments, the pharmaceutical and/or nutraceutical agent isacid labile. The carriers may be tailored to selectively minimizerelease of the acid labile active agents in the stomach and selectivelytarget release of the acid labile active agent to the small intestinesor the large intestines. This embodiment could be especially useful forpatients at risk for cardiovascular (CV) disease and acid refluxdisease, or an elevated risk of gastrointestinal bleeding that requirethe use of a proton pump inhibitor including but not limited toomeprazole or lansoprazole.

In other embodiments, the carriers comprise a least one targeted releaseagent, where the carrier composition and/or its components are capableof controllably releasing at least one active agent into certainportions of the gastro-intestinal (GI) tract. In other embodiments, thetargeted release agents comprise pH dependent release agents capable ofcontrollably releasing the active agents in a pH dependent manner. Inother embodiments, the targeted release agents comprise pH dependentrelease agents capable of controllably releasing the active agents intocertain portions of the GI tract based on a pH of the portions. In otherembodiments, the pH dependent release agents include fatty acid havingat least 8 carbon atoms. In other embodiments, the carrier furthercomprising at least one neutral lipid, where the neutral lipid is waterimmiscible. In other embodiments, the neutral lipids comprisemono-glycerides, diglycerides, triglycerides, or mixtures andcombinations thereof, where the ester side chains have at least 6 carbonatoms. In other embodiments, carrier further comprising less than 10 wt.% of a phospholipid or a plurality of phospholipids.

Some embodiments of the present disclosure relate to a carriercomposition comprising up to 80 wt. % one or more free fatty acids, upto 40 wt. % of a mixture of at least one nonionic surfactants and acationic surfactant, an anionic surfactant, or a zwitterionicsurfactant, and up to 50 wt. % one or more neutral lipids, where thecarrier composition and/or its components are capable of controllablyreleasing at least one active agent into certain portions of thegastrointestinal (GI) tract. In some embodiments, the mixture ofsurfactants comprises at least one nonionic surfactant and at least onecationic, anionic, or zwitterionic surfactant is a weight ratio of theat least one nonionic surfactant to the at least one cationic, anionic,or zwitterionic surfactant between about 50:1 and 1:1. In someembodiments, the mixture of surfactants comprises at least one nonionicsurfactant and at least one zwitterionic surfactant is a weight ratio ofnonionic surfactants to zwitterionic surfactants between about 50:1 and1:1.

Some embodiments of the present disclosure relate broadly to carriersincluding at least one targeted release agent. The carriers and/or theircomponents modify and/or alter the chemical and/or physical propertiesof biologically active agents and/or behavior of biologically activeagents in tissues and/or organs reducing and/or altering tissue and/ororgan toxicity, improving and/or altering bioavailability, and/orimproving and/or altering efficacy of biologically active agents. Incertain embodiments, the carriers and/or their components modify and/oralter the chemical and/or physical properties of biologically activeagents and/or behavior of biologically active agents in tissues and/ororgans in a pH dependent manner to reduce and/or alter tissue and/ororgan toxicity, improve and/or alter bioavailability, and/or improveand/or alter efficacy of biologically active agents. The carriersinclude all of the properties set forth above in addition to any otherset forth below.

In certain embodiments, the carriers include: (1) pH dependent releasesystem, (2) a pH dependent carrier reassembly/assembly and biologicallyactive agent reabsorption/absorption due to duodenal reflux, (3)optionally one or more neutral lipids, (4) optionally one or moresurfactants, (5) optionally a biologically active agent complexingagent, and (6) optionally a protective system including agents to reduceand/or eliminate biologically active agent toxicities, irritations orside effects. The carriers are generally viscous fluids capable of beingorally administered, directly administered, internally administeredand/or topically administered.

In other embodiments, the carriers may also include other componentssuch as: (1) excipients, (2) adjuvants, (3) drying agents, (4)antioxidants, (5) preservatives, (6) chelating agents, (7)viscomodulators, (8) tonicifiers, (9) flavorants and taste maskingagents, (10) colorants, (11) odorants, (12) opacifiers, (13) suspendingagents, (14) binders, and (15) mixtures thereof.

The carriers disclosed herein are generally fluid and the compositionmade therefrom are generally solutions, pastes, semi-solids,dispersions, suspensions, colloidal suspensions or mixtures thereof andare capable of being orally administered, parenterally administered ortopically administered. In some embodiments, the other componentsinclude citric acid.

Some embodiments of the present disclosure broadly relate topharmaceutical carrier compositions comprising: (a) a non-aqueous pHdependent release system; and (b) a non-aqueous pH dependentreassembly/assembly and reabsorption/absorption system, wherein thecarrier composition has a low pH form and a high pH form, wherein thecarrier composition is formulated to release one or more biologicallyactive agents minimally from its low pH form and maximally from its highpH form due to the non-aqueous pH dependent release system, wherein thecarrier composition is formulated to either reassembly into its low pHform or assembly into a new low pH form due to non-aqueous pH dependentreassembly/assembly and reabsorption/absorption system, and wherein thecarrier is formulated to either reabsorb the one or more biologicallyactive agents in its reassembled form or absorb the one or morebiologically active agents in its newly assembly form. In certainembodiments, the non-aqueous pH dependent release system is present inan amount between 10 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 90 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 20 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 80 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 30 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 70 wt. %. In otherembodiments, the non-aqueous pH dependent release system is present inan amount between 40 wt. % and 95 wt. %; and the non-aqueous pHdependent reassembly/assembly and reabsorption/absorption system ispresent in an amount between about 5 wt. % and 60 wt. %. In someembodiments, when the carrier also comprises other components such as:(1) excipients, (2) adjuvants, (3) drying agents, (4) antioxidants, (5)preservatives, (6) chelating agents, (7) viscomodulators, (8)tonicifiers, (9) flavorants and taste masking agents, (10) colorants,(11) odorants, (12) opacifiers, (13) suspending agents, (14) binders,and (15) mixtures thereof, the total weight percentage of these othercomponents along with that of the non-aqueous pH dependent releasesystem and the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system is 100 wt. %.

In other embodiments, the non-aqueous pH dependent release systemcomprises: at least wt. % of one or more monocarboxylic acids having atleast 8 carbon atoms, at least 20 wt. % of one or more monocarboxylicacids having at least 8 carbon atoms, or at least 30 wt. % of one ormore monocarboxylic acids having at least 8 carbon atoms.

In other embodiments, the non-aqueous pH dependent release systemcomprises: at least wt. % of a mixture of (a) one or more low meltingpoint monocarboxylic acids, (b) one or more medium melting pointmonocarboxylic acids, (c) one or more high melting point monocarboxylicacids, or (d) any combination thereof, wherein the low melting pointmonocarboxylic acids have melting point temperatures less than or equalto room temperature, wherein the medium melting point monocarboxylicacids have melting point temperatures greater than room temperature andless than or equal to a body temperature of an animal, a mammal, or ahuman, and wherein the high melting point monocarboxylic acids havemelting point temperatures above the body temperature of an animal, amammal, or a human. In other embodiments, the non-aqueous pH dependentrelease system further comprises one or more neutral lipids. In otherembodiments, the non-aqueous pH dependent release system furthercomprises: a mixture of (a) one or more low melting point neutrallipids, (b) one or more medium melting point neutral lipids, (c) one ormore high melting point neutral lipids, or (d) any combination thereof,wherein the at low melting point neutral lipids have melting pointtemperatures less than or equal to room temperature, wherein the mediummelting point neutral lipids have melting point temperatures greaterthan room temperature and less than or equal to a body temperature of ananimal, a mammal, or a human, and wherein the high melting point neutrallipids have melting point temperatures greater than the body temperatureof an animal, a mammal, or a human.

In some embodiments, the base carriers of this disclosure include: (1)at least 10 wt. % of a non-aqueous pH dependent release system such as amixture of free fatty acids; and (2) one or more reconstituting agents(i.e., compounds contributing to pH dependent reassembly/reabsorption).

In certain embodiments, the carrier may include one or more of thefollowing additives: (a) one or more excipients, (b) one or moreadjuvants, (c) one or more drying agents, (d) one or more antioxidants,(e) one or more preservatives, (f) one or more chelating agents, (g) oneor more viscomodulators, (h) one or more tonicifiers, (i) one or moreflavorants, (j) one or more colorants, (k) one or more odorants, (l) oneor more opacifiers, (m) one or more of suspending agents, and (n)mixtures thereof.

TABLE A Reagent wt. % range Base Carrier pH dependent release system 10to 90 reconstituting agents 90 to 10 Additive Weight Percentages Basedon 100% of Base Carrier complexing agent 0 to 10 Excipients 0 to 5 Adjuvants 0 to 5  drying agents 0 to 5  Antioxidants 0 to 5 Preservatives 0 to 5  chelating agents 0 to 5  Viscomodulators 0 to 5 Opacifiers 0 to 5  suspending agents 0 to 5 

The carriers and/or the carrier components are designed to modify and/oralter the chemical and/or physical properties and/or behavior of atleast one active agent in tissues and/or organs reducing and/or alteringtissue and/or organ toxicity, improving and/or altering bioavailability,and/or improving and/or altering efficacy. In certain embodiments, thecarriers and/or the biocompatible, hydrophobic agents modify and/oralter the chemical and/or physical properties and/or behavior of atleast one active agent in tissues and/or organs in a pH dependent mannerto reduce and/or alter tissue and/or organ toxicity, improve and/oralter bioavailability, and/or improve and/or alter efficacy. Thecarriers and/or carrier components are also designed to facilitatereconstitution of any carrier blow back from the duodenum to stomach anddrug reabsorption of the blow back material.

It is believed that the carriers and/or their components interact withcertain types of biologically active agents to affect particle size,morphology, other physical characteristics, physical/chemical propertiesand/or behavior and physical/chemical properties of the crystals of theactive agent in the carrier. In certain embodiments, the biologicallyactive agents are added to the carrier at an elevated temperature, wherethe temperature may be up to the melting temperature of the activeingredient, but below a decomposition temperature of any of the carriercomponents or biologically active agents. The inventors believe that theaugmented properties result in increased bioavailability of thebiologically active agents once the pH of the environment is at or nearthe pKa or pKb of the pH dependent release agents and/or thebiologically active agents.

III. pH Dependent Release Agents

pH dependent release compounds, as disclosed herein, generally includeat least one ionizable group, i.e., a group that undergoes a change inat least one chemical property in a pH dependent manner. For example,carboxylic acids exist in two form depending on pH, a normal acid form,R—COOH, in pH environments below the acids' pKa values and a salt form,R—COO-A+, where A+ is a counterion, in environments at or above theacid's pKa values. Exemplary examples of other ionizable groups usefulin the present carriers include, without limitation, a hydroxy group, anamino group, an amide group, other similarly ionizable groups, ormixtures and combinations thereof of these ionizable group withcarboxylic acid groups. The targeted release agents are generallyimmiscible or insoluble in water and are generally soluble or misciblein oils. In certain embodiments, the compounds may be weak carboxylicacids such as fatty acids, i.e., acids that have a pKa value greaterthan or equal to about pH 3.5.

For targeted release agents that include groups that may be deprotonatedsuch as COOH and OH groups, the targeted release agents are neutralbelow their pKa values, especially at pH values less than pH 3, and areionized at pH values at or above their pKa values. More particularly,the targeted release agents are neutral in gastric fluid and ionized(deprotonated) in duodenum fluid. Such weak acid targeted release agentsionize as the pH rises converting them into surfactants, which assist ina rapid dissolution of the carrier releasing the biologically activeagent or API in higher pH environments. Because the GI tract has a pHprofile starting at the stomach and proceeding to the large intestinesof increasing pH from a pH value in the stomach between about pH 1 andabout pH 3 to a pH in the duodenum between about pH 3 and pH 7 to pHvalues as high as pH 8 or 9 in the large intestines, compositions may beformulated to release the biologically active agents at different pHvalues based on the pKa values of the release agents. Thus, the carriersdisclosed herein are designed to efficiently and rapidly release abiologically active agents only when the pH of the environment is at orgreater than the pKa value of the release agents. The carriers of thisdisclosure may include from an effective amount of the release agents to100% of release agents. Fatty acids represent one class of targetedrelease agents that are immiscible in water and have pKa valuesgenerally greater than about pH 3 and are converted to surfactants uponionization at pH values at or above their pKa values.

Free Fatty Acids

Suitable biocompatible fatty acids for use in this disclosure include,without limitation, any saturated fatty acid or unsaturated fatty acidsor mixtures or combinations thereof suitable for a human, mammal oranimal consumption. Exemplary fatty acids include short chain free fattyacids (SCFFA), medium chain free fatty acids (MCFFA), long chain freefatty acids (LCFFA), very long-chain free fatty acids (VLCFFA) andmixtures or combinations thereof. SCFFA include free fatty acids havinga hydrocarbyl tail group having 4 to 7 carbon atoms (C4 to C7). MCFFAinclude free fatty acids having a hydrocarbyl group having 8 to 13carbon atoms (C8 to C13). LCFFA include free fatty acids having ahydrocarbyl group having 14 to 24 carbon atoms (C14-C24). VLCFFA includefree fatty acids having a hydrocarbyl group having greater than 24carbon atoms (>C24). Exemplary unsaturated fatty acids include, withoutlimitation, myristoleic acid [CH₃(CH₂)₃CH═CH(CH₂)₇COOH, cis-Δ9, C:D14:1, n-5], palmitoleic acid [CH₃(CH₂)₅CH═CH(CH₂)₇COOH, cis-Δ9, C:D16:1, n-7], sapienic acid [CH₃(CH₂)₈CH═CH(CH₂)₄COOH, cis-Δ6, C:D 16:1,n-10], oleic acid [CH₃(CH₂)₇CH═CH(CH₂)₇COOH, cis-Δ9, C:D 18:1, n-9],linoleic acid [CH₃(CH₂)₄CH═CHCH₂CH═CH(CH₂)₇COOH, cis,cis-Δ9,Δ12, C:D18:2, n-6], α-Linolenic acid [CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₇COOH,cis,cis,cis-Δ9,Δ12,Δ15, C:D 18:3, n-3], arachidonic acid[CH₃(CH₂)₄CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₃COOH,cis,cis,cis,cis-Δ,Δ8,Δ11,Δ14, C:D 20:4, n-6], eicosapentaenoic acid[CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₃COOH],cis,cis,cis,cis,cis-Δ5,Δ8,Δ11,Δ14,Δ17, 20:5, n-3], erucic acid[CH₃(CH₂)₇CH═CH(CH₂)₁₁COOH, cis-Δ13, C:D 22:1, n-9], docosahexaenoicacid [CH₃CH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CHCH₂CH═CH(CH₂)₂COOH,cis,cis,cis,cis,cis,cis-Δ4,Δ7,Δ10,Δ13,Δ16,Δ19, C:D 22:6, n-3], ormixtures and combinations thereof.

Exemplary saturated fatty acids include, without limitation, lauric acid[CH₃(CH₂)₁₀COOH, C:D 12:0], myristic acid [CH₃(CH₂)₁₂COOH, C:D 14:0],palmitic acid [CH₃(CH₂)₁₄COOH, C:D 16:0], stearic acid [CH₃(CH₂)₁₆COOH,C:D 18:0], arachidic acid [CH₃(CH₂)₁₈COOH, C:D 20:0], behenic acid[CH₃(CH₂)₂₀COOH, C:D 22:0], lignoceric acid [CH₃(CH₂)₂₂COOH, C:D 24:0],cerotic acid [CH₃(CH₂)₂₄COOH, C:D 26:0], or mixture or combinationsthereof.

Exemplary saturated fatty acids include, without limitation, butyric(C4), valeric (C5), caproic (C6), enanthic (C7), caprylic (C8),pelargonic (C9), capric (C10), undecylic (C11), lauric (C12), tridecylic(C13), myristic (C14), pentadecylic (C15), palmitic (C16), margaric(C17), stearic (C18), nonadecylic (C19), arachidic (C20), heneicosylic(C21), behenic (C22), tricosylic (C23), lignoceric (C24), pentacosylic(C25), cerotic (C26), heptacosylic (C27), montanic (C28), nonacosylic(C29), melissic (C30), hentriacontylic (C31), lacceroic (C32), psyllic(C33), geddic (C34), ceroplastic (C35), hexatriacontylic (C36),heptatriacontylic acid (C37), octatriacontylic acid (C38),nonatriacontylic acid (C39), tetracontylic acid (C40), and mixtures orcombinations thereof. Unsaturated fatty acids include, withoutlimitation, n-3 unsaturated fatty acids such as α-linolenic acid,stearidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, n-6unsaturated fatty acids such as linoleic acid, γ-linolenic acid,dihomo-γ-linolenic acid, and arachidonic acid, n-9 unsaturated fattyacids oleic acid, elaidic acid, eicosenoic acid, erucic acid, nervonicacid, mead acid and mixtures or combinations thereof.

Exemplary unsaturated fatty acids include, without limitation, (a) ω-3unsaturated fatty acids such as octenoic (8:1), decenoic (10:1),decadienoic (10:2), lauroleic (12:1), laurolinoleic (12:2),myristovaccenic (14:1), myristolinoleic (14:2), myristolinolenic (14:3),palmitolinolenic (16:3), palmitidonic (16:4), α-linolenic (18:3),stearidonic (18:4), dihomo-α-linolenic (20:3), eicosatetraenoic (20:4),eicosapentaenoic (20:5), clupanodonic (22:5), docosahexaenoic (22:6),9,12,15,18,21-tetracosapentaenoic (24:5),6,9,12,15,18,21-tetracosahexaenoic (24:6), and mixtures or combinationsthereof; (b) ω-5 unsaturated such as myristoleic (14:1), palmitovaccenic(16:1), α-eleostearic (18:3), β-eleostearic (trans-18:3) punicic (18:3),7,10,13-octadecatrienoic (18:3), 9,12,15-eicosatrienoic (20:3),β-eicosatetraenoic (20:4), and mixtures or combinations thereof; (c) ω-6unsaturated such as 8-tetradecenoic (14:1), 12-octadecenoic (18:1),linoleic (18:2), linolelaidic (trans-18:2), γ-linolenic (18:3), calendic(18:3), pinolenic (18:3), dihomo-linoleic (20:2), dihomo-γ-linolenic(20:3), arachidonic (20:4), adrenic (22:4), osbond (22:5), and mixturesor combinations thereof; (d) ω-7 unsaturated such as palmitoleic (16:1),vaccenic (18:1), rumenic (18:2), paullinic (20:1),7,10,13-eicosatrienoic (20:3), and mixtures or combinations thereof; (e)ω-9 Unsaturated such as oleic (18:1), elaidic (trans-18:1), gondoic(20:1), erucic (22:1), nervonic (24:1), 8,11-eicosadienoic (20:2), mead(20:3), and mixtures or combinations thereof; (f) ω-10 Unsaturated suchas Sapienic (16:1); (g) ω-11 unsaturated such as gadoleic (20:1); (h)ω-12 Unsaturated such as 4-Hexadecenoic (16:1) Petroselinic (18:1)8-Eicosenoic (20:1), and mixtures or combinations thereof; and (i)mixtures or combinations thereof.

Diacids

Exemplary examples of saturate diacids include, without limitation,ethanedioic acid (oxalic acid), propanedioic acid (malonic acid),butanedioic acid (succinic acid), pentanedioic acid (glutaric acid),hexanedioic acid (adipic acid), heptanedioic acid (pimelic acid),octanedioic acid (suberic acid, nonanedioic acid (azelaic acid),decanedioic acid (sebacic acid), undecanedioic acid, dodecanedioic acid,tridecanedioic acid (brassylic acid), hexadecanedioic acid (thapsicacid), heneicosa-1,21-dioic acid (japanic acid), docosanedioic acid(phellogenic acid), triacontanedioic acid (equisetolic acid), andmixtures or combinations thereof. Exemplary examples of unsaturateddiacids include, without limitation, (Z)-butenedioic acid (maleic acid),(E)-butenedioic acid (fumaric acid), (Z and E)-pent-2-enedioic acid(glutaconic acid), 2-decenedioic acid, dodec-2-enedioic acid (traumaticacid), (2E,4E)-hexa-2,4-dienedioic acid (muconic acid), and mixtures orcombinations thereof.

Poly Acids

Suitable poly carboxylic acid compounds for use a pH depending releaseagents include, without limitation, any poly carboxylic acid compound.Exemplary examples of water immiscible poly acids include, withoutlimitation, dicarboxylic acids having carbyl or carbenyl groups havingbetween 8 and 50 carbon atoms and mixtures or combinations thereof.Polymer carboxylic acids or polymers including carboxylic acid groups,where the polymers are oil soluble or are oils, not miscible with water.Exemplary example of hydrophilic poly acids include, without limitation,polyacrylic acid, polymethacrylic acid, polylactic acid, polyglycolacid, mixtures and combinations thereof, copolymers thereof, CARBOPOL®reagents available from Lubrizol Corporation (a registered trademark ofthe Lubrizol Corporation), other carboxylic acid containing polymers, ormixtures or combinations thereof.

Hydroxy Acids

Suitable hydroxy acids include, without limitation, 2-hydroxyoleic acid,2-hydroxytetracosanoic acid (cerebronic acid),2-hydroxy-15-tetracosenoic acid (hydroxynervonic acid),2-hydroxy-9-cis-octadecenoic acid, 3-hydroxypalmitic acid methyl ester,2-hydroxy palmitic acid, 10-hydroxy-2-decenoic acid,12-hydroxy-9-octadecenoic acid (ricinoleic acid),1,13-dihydroxy-tetracos-9t-enoic acid (axillarenic acid),3,7-dihydroxy-docosanoic acid (byrsonic acid),9,10-dihydroxyoctadecanoic acid, 9,14-dihydroxyoctadecanoic acid,22-hydroxydocosanoic acid (phellonic acid),2-oxo-5,8,12-trihydroxydodecanoic acid (phaseolic acid),9,10,18-trihydroxyoctadecanoic acid (phloionolic acid),7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid (Maresin 1),5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (resolvinE1), resolvin D1, 10,17S-docosatriene, (neuroprotectin D1).

Fatty Acid Salts

Suitable biocompatible fatty acid salts for use in this disclosureinclude, without limitation, alkali metal salts of any of the abovelisted fatty acids, alkaline earth metals salts of any of the abovelisted fatty acids, transition metal salts of any of the above listedfatty acids or mixture or combinations thereof. In certain embodiments,the metal salts include lithium, sodium, potassium, cesium, magnesium,calcium, barium, copper, zinc, cobalt, iron, or mixture or combinationsthereof.

Polymer Including Carboxylic Acids

Suitable water insoluble polymer including carboxylic acids include,without limitation, homo acrylic acid polymers, acrylic acid/acrylatecopolymers, ethylene/acrylic acid copolymers, propylene/acrylic acidcopolymers, unsaturated olefinic monomer/acrylic acid copolymers,methacrylic acid/acrylic acid copolymers, methacrylic acid/acrylatecopolymers, ethylene/methacrylic acid copolymers, propylene/methacrylicacid copolymers, unsaturated olefinic monomer/methacrylic acidcopolymers, acrylic acid/methacrylic acid/unsaturated olefinic monomercontaining polymers, acid functionalized cellulose polymers, or mixturesand combinations thereof. Exemplary examples include, withoutlimitation, poly(methacrylic acid-co-methyl methacrylate) (EUDRAGIT® L,S and F), hydroxypropylmethylcellulose phthalate (HPMC-P) and HPMCacetate succinate (HPMC-AS), which possess carboxyl groups on thepolymer side chains, are insoluble at stomach low pH, but soluble atintestinal neutral pH.

In some embodiments, the carrier comprises one or more pH dependentrelease compounds in an amount of at least 5 wt. %. This includes anamount of at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 wt. % or more,including increments therein. In some embodiments, the carrier comprisesone or more pH dependent release compounds in an amount of at least 10wt. % or at least 15 wt. % or at least 20 wt. %. In some embodiments,the carrier comprises one or more pH dependent release compounds in anamount of about 5 wt. % to about 50 wt. %. This includes an amount ofabout 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 wt. %, including incrementstherein. In some embodiments, the carrier comprises one or more pHdependent release compounds in an amount of about 5 wt. % to about 45wt. %, about 5 wt. % to about 40 wt. %, about 10 wt. % to about 50 wt.%, about 10 wt. % to about 45 wt. %, about 10 wt. % to about 40 wt. %,about 15 wt. % to about wt. %, about 15 wt. % to about 45 wt. %, about15 wt. % to about 40 wt. %, about 20 wt. % to about 50 wt. %, about 20wt. % to about 45 wt. %, about 20 wt. % to about 40 wt. %, about 25 wt.% to about 50 wt. %, about 25 wt. % to about 45 wt. %, or about 25 wt. %to about 40 wt. %.

In some embodiments, the carrier comprises a carboxylic acid having atleast 8 carbon atoms in an amount of at least 5 wt. %. This includes anamount of at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 wt. % or more,including increments therein. In some embodiments, the carrier comprisesa carboxylic acid having at least 8 carbon atoms in an amount of atleast 10 wt. % or at least 15 wt. % or at least 20 wt. %. In someembodiments, the carrier comprises a carboxylic acid having at least 8carbon atoms in an amount of about 5 wt. % to about 50 wt. %. Thisincludes an amount of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 wt. %,including increments therein. In some embodiments, the carrier comprisesa carboxylic acid having at least 8 carbon atoms in an amount of about 5wt. % to about 45 wt. %, about 5 wt. % to about 40 wt. %, about 10 wt. %to about 50 wt. %, about 10 wt. % to about 45 wt. %, about 10 wt. % toabout 40 wt. %, about 15 wt. % to about 50 wt. %, about wt. % to about45 wt. %, about 15 wt. % to about 40 wt. %, about 20 wt. % to about 50wt. %, about 20 wt. % to about 45 wt. %, about 20 wt. % to about 40 wt.%, about 25 wt. % to about 50 wt. %, about 25 wt. % to about 45 wt. %,or about 25 wt. % to about 40 wt. %.

In some embodiments, the non-aqueous carrier comprises a pH dependentreleasing agent that has a low melting point (i.e., a temperature lessthan or equal to room temperature). In some embodiments, the pHdependent releasing agent has a melting point below 25° C. In someembodiments, the pH dependent releasing agent has a melting point below20° C. In some embodiments, the pH dependent releasing agent has amelting point below 15° C. In some embodiments, the pH dependentreleasing agent has a melting point below 10° C. In some embodiments,the pH dependent releasing agent has a melting point below 5° C. In someembodiments, the pH dependent releasing agent has a melting point below0° C. In some embodiments, the pH dependent releasing agent is acarboxylic acid having at least 8 carbon atoms. In some embodiments, thecarboxylic acid having at least 8 carbon atoms is a monocarboxylic acid.

In some embodiments, the pH dependent release agent has a medium meltingpoint (i.e., melting point temperatures greater than room temperatureand less than or equal to a body temperature of an animal, a mammal, ora human). In some embodiments, the melting point of the agent is aboveroom temperature and less than or equal to a body temperature of amammal. In some embodiments, the melting point of the agent is aboveroom temperature and less than or equal to a body temperature of ahuman. In some embodiments, the pH dependent releasing agent has amelting point above 25° C. and below 37° C. In some embodiments, the pHdependent releasing agent has a melting point below 37° C. and above 30°C. In some embodiments, the pH dependent releasing agent has a meltingpoint below 30° C. and above 25° C. In some embodiments, the pHdependent releasing agent is a carboxylic acid having at least 8 carbonatoms. In some embodiments, the carboxylic acid having at least 8 carbonatoms is a monocarboxylic acid.

In some embodiments, the pH dependent releasing agent has a high meltingpoint (i.e., the melting point is above the body temperature of ananimal, a mammal, or a human). In some embodiments, the pH dependentreleasing agent has a melting point above 37° C. In some embodiments,the pH dependent releasing agent has a melting point above 40° C. Insome embodiments, the pH dependent releasing agent has a melting pointabove 45° C. In some embodiments, the pH dependent releasing agent has amelting point above 50° C. In some embodiments, the pH dependentreleasing agent has a melting point above 55° C. In some embodiments,the pH dependent releasing agent has a melting point above 50° C. Insome embodiments, the pH dependent releasing agent has a melting pointabove 65° C. In some embodiments, the pH dependent releasing agent has amelting point above 70° C. In some embodiments, the pH dependentreleasing agent has a melting point above 75° C. In some embodiments,the pH dependent releasing agent is a carboxylic acid having at least 8carbon atoms. In some embodiments, the carboxylic acid having at least 8carbon atoms is a monocarboxylic acid.

IV. pH Dependent Assembly/Reassembly and Absorption/Reabsorption System

pH dependent assembly and/or reassembly compounds (i.e., reconstitutionagents) include groups that facilitate carrier reassembly or facilitatethe formation a new carrier upon duodenal reflux, i.e., the componentsin the carrier either assist reassembly of the carrier into its low pHform from its high pH form or the components assist assembly of thecarrier into a new carrier form in low pH environments. In either case,the reassembled carrier or newly assembled carrier is capable ofreabsorbing or absorbing the biologically active agents upon transitionfrom its high pH form to its low pH form. The absorption or reabsorptionof the biologically active agents has a number of advantageousproperties: (a) further protection of the stomach from biologicallyactive agents injurious to the stomach, and (b) further prevention ofthe loss of biologically active agents due to decomposition in thestomach, e.g., reduced loss of acid labile biologically active agents.

Exemplary pH dependent reassembly compounds include, without limitation,neutral lipids, surfactants, polymers including ionizable groups, othercompound capable of carrier reassembly or capable of new carrierformation in low pH environments that tend to absorb or reabsorbbiologically active agents, or mixtures and combinations thereof. Ofcourse, the pH dependent assembly or reassembly compounds should beselected that do not adversely affect the pH dependent releaseproperties of the carrier.

In some embodiments, reconstituting agents are designed to eitherfacilitate oil matrix reconstitution and/or facilitate drug reabsorptioninto reconstituted carrier such as sorbitan and/or sorbitol esters,poloxamers, nonionic neutral polymers, and mixtures of combinationsthereof.

In other embodiments, the non-aqueous pH dependent reassembly/assemblyand reabsorption/absorption system comprises: (a) one or more polyacids,(b) one or more polymers including a plurality of carboxylic acidmoieties, (c) one or more water insoluble surfactants, (d) one or morewater insoluble oligomers or lower molecular weight polymers, (e) one ormore water insoluble polymers (higher molecular weight polymers than theoligomer), and (f) any combination thereof. In some embodiments, thenon-aqueous pH dependent reassembly/assembly and reabsorption/absorptionsystem comprises: (a) one or more polyacids, (b) one or more waterinsoluble oligomers (lower molecular weight polymers), (c) one or morewater insoluble polymers (higher molecular weight polymers than theoligomer), and (d) any combination thereof.

In some embodiments, the non-aqueous pH dependent reassembly/assemblyand reabsorption/absorption system comprises one or more surfactants(e.g., nonionic surfactants and/or zwitterionic surfactants), one ormore neutral lipids, and optionally: (a) one or more polyacids, (b) oneor more water insoluble oligomers (lower molecular weight polymers), (c)one or more water insoluble polymers (higher molecular weight polymersthan the oligomer), and (d) any combination thereof.

In some embodiments, the one or more polyacids comprise a biocompatiblefatty poly acid. In some embodiments, the one or more polyacids compriseglutaric acid (GA), poly(methacrylic acid-co-methyl methacrylate), orhypromellose phthalate (HPMC-P), or a combination of two or morethereof.

In some embodiments, the one or more polyacids are present in thecarrier in an amount of about 1 wt. % to about 10 wt. %. This includesabout 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt. % of the carrier, includingincrements therein.

In some embodiments, the one or more water insoluble oligomers compriselow molecular weight poly(hexyl substituted lactides) (PHLA) (e.g.,having between 10 and 100 hexyl substituted lactide units), lowmolecular weight polyethylene (e.g., having between 10 and 100 ethyleneunits), polyvinyl chloride, ethyl cellulose, or acrylate polymers andcopolymers thereof, or a combination of two or more thereof.

In some embodiments, the one or more water insoluble oligomers arepresent in the carrier in an amount of about 1 wt. % to about 5 wt. %.This includes about 1.0, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.0,3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, or 5.0 wt. % of the carrier,including increments therein.

In some embodiments, the one or more water insoluble polymers comprise acopolymer of ethyl acrylate and methyl methacrylate,lactide-coglycolide, cellulose, or ethyl cellulose, or a combination oftwo or more thereof.

In some embodiments, the one or more water insoluble polymers arepresent in the carrier in an amount of about 1 wt. % to about 5 wt. %.This includes about 1.0, 1.25, 1.50, 1.75, 2.0, 2.25, 2.50, 2.75, 3.0,3.25, 3.50, 3.75, 4.0, 4.25, 4.50, 4.75, or 5.0 wt. % of the carrier,including increments therein.

It has been found that free fatty acids are subject to esterification inthe duodenum. If this process is facile, then considerable free fattyacid would be lost in the duodenum reducing the ability for matrix toreform and absorb BAI with minimal loss of BAI once reabsorbed. Theseadditives including a plurality of carboxylic acid moieties are designedto act as sacrificial agents to reduce the amount of free fatty acidfrom being esterified in the duodenum allowing the reassembly of the oilmatrix with sufficient free fatty acid to minimize loss of absorbed BAI.The water insoluble surfactants, especially nonionic surfactants, arebelieved to be capable of stabilizing oil matrices, especially duringreassembly or reformation due to duodenal reflux. In an analogousmanner, the water insoluble oligomers or polymers are also believed tostabilize oil matrices, especially during reassembly or reformation dueto duodenal reflux. Thus, by engineering the carrier to include one ormore of these agents, the matrix structure may be stabilized initiallyand more importantly during reconstitution.

In other embodiments, the carrier further comprise less than 10 wt. % ofone or more selected from (1) fatty acid salts, (2) secondary complexingagents, (3) protective agents, (4) excipients, (5) adjuvants, (6) dryingagents, (7) antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders. This includes an amount of about 9, 8, 7, 6,5, 4, 3, 2, 1, 0.8, 0.5, 0.3, 0.1, 0.08, 0.05, 0.03 wt. % of thecarrier, or less, including increments therein.

In some embodiments, the reconstitution agent comprises one or morepolyacids. In some embodiments, the polyacid is a biocompatible fattypoly acid.

In some embodiments, the reconstitution agent comprises one or morepolymers including a plurality of carboxylic acid moieties. In someembodiments, the reconstitution agent comprises one or more surfactants.

In some embodiments, the reconstitution agent comprises one or morewater insoluble oligomers. In some embodiments, a water-insolubleoligomer is a pre-polymer having 2 to about 15 recurring monomericunits, which can be the same or different. Exemplary examples including,without limitation, low molecular weight poly(hexyl substitutedlactides) (PHLA), low molecular weight polyethylene, polyvinyl chloride,ethyl cellulose, acrylate polymers and copolymers thereof.

In some embodiments, the reconstitution agent comprises one or morewater insoluble polymers. In some embodiments, a water insoluble polymeris based on acrylic of methacrylic esters. In some embodiments, the oneor more water insoluble polymers include EUDRAGIT® L30D a copolymer ofmethacrylic acid and ethyl acrylate. In some embodiments, the one ormore water insoluble polymers include EUDRAGIT® NE30D a copolymer ofethyl acrylate and methyl methacrylate. In some embodiments, the waterinsoluble polymer is a biodegradable polymer. In some embodiments, thewater insoluble polymer includes lactide-coglycolide. In someembodiments, the water-insoluble polymer is selected from cellulose andethyl cellulose.

In some embodiments, the non-aqueous carrier comprises a reconstitutionagent that has a low melting point (i.e., a temperature less than orequal to room temperature). In some embodiments, the reconstitutionagent has a melting point below 25° C. In some embodiments, thereconstitution agent has a melting point below 20° C. In someembodiments, the reconstitution agent has a melting point below 15° C.In some embodiments, the reconstitution agent has a melting point below10° C. In some embodiments, the reconstitution agent has a melting pointbelow 5° C. In some embodiments, the reconstitution agent has a meltingpoint below 0° C.

In some embodiments, the reconstitution agent has a medium melting point(i.e., melting point temperatures greater than room temperature and lessthan or equal to a body temperature of an animal, a mammal, or a human).In some embodiments, the melting point of the agent is above roomtemperature and less than or equal to a body temperature of a mammal. Insome embodiments, the melting point of the agent is above roomtemperature and less than or equal to a body temperature of a human. Insome embodiments, the reconstitution agent has a melting point above 25°C. and below 37° C. In some embodiments, the reconstitution agent has amelting point below 37° C. and above 30° C. In some embodiments, thereconstitution agent has a melting point below 30° C. and above 25° C.

In some embodiments, the reconstitution agent has a high melting point(i.e., the melting point is above the body temperature of an animal, amammal, or a human). In some embodiments, the reconstitution agent has amelting point above 37° C. In some embodiments, the reconstitution agenthas a melting point above 40° C. In some embodiments, the reconstitutionagent has a melting point above 45° C. In some embodiments, thereconstitution agent has a melting point above 50° C. In someembodiments, the reconstitution agent has a melting point above 55° C.In some embodiments, the reconstitution agent has a melting point above50° C. In some embodiments, the reconstitution agent has a melting pointabove 65° C. In some embodiments, the reconstitution agent has a meltingpoint above 70° C. In some embodiments, the reconstitution agent has amelting point above 75° C.

Fatty Acid, Fatty Acid Ester, and Triglyceride Melting Point Data: Thefollowing tables list physical properties, especially melting pointtemperatures of a number of fatty acids, fatty acid esters, andtriglycerides for use in the present disclosure.

TABLE I Melting Point Data (° C.) for Certain Free Fatty Acids mp NameFormula Structural Formula (° C.) lauric acid C₁₁H₂₃COOH CH₃(CH₂)₁₀COOH44 myristic acid C₁₃H₂₇COOH CH₃(CH₂)₁₂COOH 58 palmitic acid C₁₅H₃₁COOHCH₃(CH₂)₁₄COOH 63 palmitoleic C₁₅H₂₉COOH CH₃(CH₂)₅CH—CH(CH₂)₇COOH 0.5acid stearic acid C₁₇₁H₃₅COOH CH₃(CH₂)₁₆COOH 70 oleic acid C₁₇H₃₃COOHCH₃(CH₂)₇CH═CH(CH₂)₇COOH 16 linoleic acid C₁₇H₃₁COOHCH₃(CH₂)₃(CH₂CH═CH)₂(CH₂)₇COOH −5 α-linolenic C₁₇H₂₉COOHCH₃(CH₂CH—CH)₃(CH₂)₇COOH −11 acid arachidonic C₁₉H₃₁COOHCH₃(CH₂)₄(CH₂CH—CH)₄(CH₂)₂COOH −50 acid

TABLE II Melting Point Data (° C.) of Saturated Free Fatty Acids andFatty Acid Esters Free Methyl Ethyl Propyl Butyl Chain Fatty Acid EsterEster Ester Ester  8:0 15.41 −37.43 −44.74 −45.68 −43.33  9:0 11.28−34.99 −43.56 −41.81 −43.10 10:0 30.80 −13.48 −20.44 −21.84 −22.96 11:027.32 −12.17 −19.43 −19.70 −23.69 12:0 43.29 4.30 −1.78 −4.35 −6.53 13:041.37 5.17 −2.07 −8.48 14:0 53.47 18.09 12.52 9.24 5.57 15:0 52.15 18.4711.81 6.26 16:0 62.20 28.48 23.23 20.27 16.07 17:0 60.85 28.58 24.7022.32 19.68 18:0 69.29 37.66 32.98 28.10 25.63 19:0 67.76 38.03 35.2832.94 30.71 20:0 74.76 46.43 41.33 37.15 35.14 21:0 73.69 47.58 43.6622:0 79.54 53.22 48.64 45.29 23:0 78.74 53.38 51.22 24:0 83.82 58.6155.92 52.32

TABLE III Melting Point Data (° C.) of Unsaturated Free Fatty Acids andFatty Acid Esters Methyl Ethyl Propyl Butyl Chain FFA Ester Ester EsterEster 11:1 Δ10 23.91 −24.63 −32.24 14:1 Δ9c −3.91 −52.26 −65.35 −66.1916:1 Δ9c 1.22 −34.10 −36.65 −52.61 16:1 Δ9t 32.22 −2.99 −10.99 −12.8317:1 Δ10c 15.05 −16.02 −20.02 −24.35 18:1 Δ6c 29.11 −0.97 −7.74 18:1 Δ6t52.38 19.16 9.45 18:1 Δ9c 12.82 −20.21 −20.32 −30.50 −34.76 18:1 Δ9t43.35 9.94 4.17 −0.03 18:1 Δ11c 15.40 −24.29 −36.49 18:1 Δ11t 43.37 9.944.10 −0.23 18:2 Δ9c, Δ12c −7.15 −43.09 −56.72 −51.50

TABLE IV Melting Point Data (° C.) of Unsaturated Free Fatty Acids andFatty Acid Esters Methyl Ethyl Propyl Butyl Chain FFA Ester Ester EsterEster 18:3 Δ9c, Δ12c, Δ15c −11.58 −61.71 −57.63 −58.61 19:1 Δ10c 22.47−2.33 −7.51 20:1 Δ5c 26.61 2.39 −8.57 20:1 Δ8c 35.13 9.11 3.14 20:1 Δ11c23.37 −7.79 −8.80 −22.69 20:1 Δ11t 51.94 20.76 14.11 21:1 Δ12 32.96 8.475.63 22:1 Δ13c 32.18 −3.05 22:1 Δ13t 59.16 29.36 24.50 23:1 Δ14c 43.2318.22 13.27 24:1 Δ15c 42.87 9.49 1.21

TABLE V Melting Point Data (º C.) of Some Branched Free Fatty Acids(FFA) and Fatty Acid Methyl Esters Chain FFA Methyl Ester Iso Acids10-Methyl C11 40.28 −13.02 11-Methyl C12 40.57 −6.87 12-Methyl C13 53.133.48 13-Methyl C14 51.35 6.37 14-Methyl C15 (isopalmitic) 61.94 16.8015-Methyl C16 59.78 17.55 16-Methyl C17 (isostearic) 69.23 26.8217-Methyl C18 66.34 27.98 18-Methyl C19 74.68 19-Methyl C20 72.51 36.43Anteiso Acids 12-Methyl C14 24.05 −5.29 13-Methyl C15 −13.34 14-MethylC16 37.10 7.62

TABLE VI Melting Point Data (º C.) of Certain Triglycerides Chain mpSaturated Triglycerides 8:0 9.44 9:0 9.46

TABLE VII Melting Point Data (º C.) of Certain Triglycerides Chain mpSaturated Triglycerides 10:0 30.37 11:0 27.98 12:0 46.29 13:0 44.60 14:057.35 15:0 55.46 16:0 65.45 17:0 64.11 18:0 72.67 19:0 71.31 20:0 77.6721:0 76.36 22:0 82.50 23:0 81.85 Unsaturated Triglycerides 16:1 Δ9c−22.75 18:1 Δ6c 26.24 18:1 Δ9c 3.98 18:1 Δ11c 1.04 18:2 Δ9c, Δ12c −12.7019:1 Δ10c 26.12 20:1 Δ11c 10.11 21:1 Δ12c 37.97 22:1 Δ13c 29.78 24:1Δ15c 41.43

TABLE VIII Melting Point Data (° C.) and Fatty Acid Compositions ofCertain Vegetable Oils % % % Oil MP Monounsaturated PolyunsaturatedSaturated Cottonseed Oil −48 18 54 28 Flax Seed Oil −24 21 71 8 AlmondOil −18 73 19 8 Sunflower Oil −17 20 69 11 Safflower Oil −17 14 78 8Soybean Oil −16 24 61 15 Corn Oil −11 25 61 14 Canola Oil −10 58 35 7Grapeseed Oil −10 57 29 14

TABLE IX Melting Point Data (° C.) and Fatty Acid Compositions ofCertain Vegetable Oils % % % Oil MP Monounsaturated PolyunsaturatedSaturated Rice Bran Oil −5 to −10 38 37 25 Hemp Seed Oil −8 13 63 9Olive Oil −6 79 8 11 Sesame Oil −6 40 42 14 Peanut Oil 3 48 34 18 PalmKernel Oil 24 12 2 86 Coconut Oil 25 6 2 92 Cocoa Butter 34 to 38 20 to43 0 to 5 57 to 64 Palm Oil 35 38 10 52

Surfactants

Suitable surfactants include, without limitation, cationic surfactants,anionic surfactants, nonionic surfactants, zwitterionic surfactants, andmixtures or combinations thereof.

Cationic Surfactants

Suitable cationic surfactants include, without limitation, RN⁺H₃Cl⁻(salt of a long-chain amine), RN⁺(CH₃)₃Cl⁻ (quaternary ammoniumchloride, also known as quats), and mixtures or combinations thereof.

One or more cationic surfactants may be present in the carrier in anamount of about 0.1 wt. % to about 5 wt. %. This includes an amount ofabout 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.90, 1.0, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or wt. %, includingincrements therein. In some embodiments, the one or more cationicsurfactants are present in the carrier in an amount of about 0.1 wt. %to about 4 wt. %, about 0.1 wt. % to about 3 wt. %, about 0.1 wt. % toabout 2 wt. %, about 0.1 wt. % to about 1 wt. %, about wt. % to about 5wt. %, about 0.5 wt. % to about 4 wt. %, about 0.5 wt. % to about 3 wt.%, about 0.5 wt. % to about 2 wt. %, about 1 wt. % to about 5 wt. %,about 1 wt. % to about 4 wt. %, or about 1 wt. % to about 3 wt. %.

Anionic Surfactants

Suitable anionic surfactants include, without limitation, anionicsurfactants include (a) carboxylates: alkyl carboxylates-fatty acidsalts; carboxylate fluoro surfactants, (b) sulfates: alkyl sulfates(e.g., sodium lauryl sulfate); alkyl ether sulfates (e.g., sodiumlaureth sulfate), (c) sulfonates: docusates (e.g., dioctyl sodiumsulfosuccinate); alkyl benzene sulfonates, (d) phosphate esters: alkylaryl ether phosphates; alkyl ether phosphates. Sodium lauryl sulphate BP(a mixture of sodium alkyl sulfates, mainly sodium dodecyl sulfate,C₁₂H₂₅SO₄Na⁺), alkyl sulfates, alkyltrimethylammonium bromides, andalcohol ethoxylates.

One or more anionic surfactants may be present in the carrier in anamount of about 0.1 wt. % to about 5 wt. %. This includes an amount ofabout 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.90, 1.0, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or wt. %, includingincrements therein. In some embodiments, the one or more anionicsurfactants are present in the carrier in an amount of about 0.1 wt. %to about 4 wt. %, about 0.1 wt. % to about 3 wt. %, about 0.1 wt. % toabout 2 wt. %, about 0.1 wt. % to about 1 wt. %, about wt. % to about 5wt. %, about 0.5 wt. % to about 4 wt. %, about 0.5 wt. % to about 3 wt.%, about 0.5 wt. % to about 2 wt. %, about 1 wt. % to about 5 wt. %,about 1 wt. % to about 4 wt. %, or about 1 wt. % to about 3 wt. %.

Zwitterionic Surfactants

Suitable zwitterionic surfactants include, without limitation,phospholipids, betaines, sulfobetaines, or mixtures and combinationsthereof. Exemplary examples include, without limitation, RN⁺H₂CH₂COO⁻,RN⁺(CH₃)₂CH₂CH₂SO₃ ⁻, where R is linear, branched, saturated, orunsaturated alkyl groups; linear, branched, saturated, or unsaturatedC₈-C₁₉ alkyl groups; linear, branched, saturated, or unsaturated C₂₀-C₄₀alkyl groups; sterol or steroid groups, or mixtures and combinationsthereof, CHAPS zwitterionic surfactants such as3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate or relatedCHAPSO surfactants, phospholipids, phospholipid containing oils such aslecithins, cocamidopropyl betaine, cocamidopropyl hydroxysultaine,hydroxysultaine, miltefosine, lipophilic peptitergents, or mixtures andcombinations.

One or more zwitterionic surfactants may be present in the carrier in anamount of at least wt. %. In some embodiments, the one or morezwitterionic surfactants are present in the carrier in an amount of atleast 10 wt. %. In some embodiments, the one or more zwitterionicsurfactants are present in the carrier in an amount of about 5 wt. % toabout 25 wt. %. This includes about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 wt. %, includingincrements therein. In some embodiments, the one or more zwitterionicsurfactants are present in the carrier in an amount of about 10 wt. % toabout 25 wt. %, or about 15 wt. % to about 25 wt. %.

In some embodiments, the one or more zwitterionic surfactants arepresent in the carrier in an amount of less than about 10 wt %. Thisincludes about 9, 8, 7, 6, 5, 4, 3, 2, 1 wt. %, or less, includingincrements therein. In some embodiments, the carrier is devoid ofzwitterionic surfactants. In some embodiments, the carrier includes lessthan 10 wt. %, or less than 5 wt. %, or less than 2.5 wt. % of one ormore phospholipids.

Phospholipids

Suitable secondary complexing agents and/or secondary anti-toxicityagents for use in the compositions of this disclosure include, withoutlimitation, phospholipids, amphoteric agents and/or zwitterionic agentsor mixtures or combinations thereof. Phospholipids include anyphospholipid or mixtures and combinations thereof such as (1)diacylglyceride phospholipids or glycerophospholipids including, withoutlimitation, phosphatidic acid (phosphatidate) (PA),phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin)(PC), phosphatidylserine (PS), phosphoinositides such asphosphatidylinositol (PI), phosphatidylinositol phosphate (PIP),phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositoltriphosphate (PIP3), and (2) phosphosphingolipids such as ceramidephosphorylcholine (Sphingomyelin) (SPH), ceramide phosphorylethanolamine(Sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol. Amphotericagents include acetates, betaines, glycinates, imidazolines,propionates, other amphoteric agents or mixtures thereof. Zwitterionicagents include, without limitation, biocompatible zwitterionicphospholipids, biocompatible zwitterionic betaines, biocompatibleamphoteric/zwitterionic surfactants, biocompatible quaternary salts,biocompatible amino acids, other biocompatible compounds capable offorming or in the form of a zwitterion, and mixtures or combinationsthereof.

Suitable biocompatible zwitterionic phospholipids for use in thisdisclosure include, without limitation, a phospholipid of generalformula:

where R¹ and R² are saturated or unsaturated substitutions ranging from8 to 32 carbon atoms;R³ is H or CH₃, and X is H or COOH; and R⁴ is ═O or H₂. Mixtures andcombinations of the zwitterionic phospholipids of the general formulaand mixtures and combinations of NSAIDs can be used as well.

Exemplary examples of zwitterionic phospholipid of the above formulainclude, without limitation, phosphatidylcholines such as phosphatidylcholine (PC), dipalmitoylphosphatidylcholine (DPPC), other disaturatedphosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol,phosphatidylserines sphingomyelin or other ceramides, or various otherzwitterionic phospholipids, phospholipid containing oils such aslecithin oils derived from soy beans, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilinoleoylphosphatidylcholine (DLL-PC),dipalmitoylphosphatidylcholine (DPPC), soy phophatidylchloine (Soy-PC orPCS) and egg phosphatidycholine (Egg-PC or PCE). In DPPC, a saturatedphospholipid, the saturated aliphatic substitution R¹ and R² areCH₃(CH₂)₁₄, R³ is CH3 and X is H. In DLL-PC, an unsaturatedphospholipid, R¹ and R² are CH₃(CH₂)₄CH═CHCH₂CH═CH(CH₂)₇, R3 is CH₃ andX is H. In Egg PC, which is a mixture of unsaturated phospholipids, R¹primarily contains a saturated aliphatic substitution (e.g., palmitic orstearic acid), and R² is primarily an unsaturated aliphatic substitution(e.g., oleic or arachidonic acid). In Soy-PC, which in addition to thesaturated phospholipids (palmitic acid and stearic acid) is a mixture ofunsaturated phospholipids (oleic acid, linoleic acid and linolenicacid). In certain embodiments, the phospholipids are zwitterionicphospholipid include, without limitation, dipalmitoylphosphatidylcholine, phosphatidyl choline, or a mixture thereof.

In some embodiments, the carrier comprises one or more zwitterionicsurfactants, wherein the one or more zwitterionic surfactants comprisephosphatidic acid, phosphatidylethanolamine, phosphatidylcholine,phosphatidylserine, phosphatidylinositol, phosphatidylinositolphosphate, phosphatidylinositol bisphosphate, phosphatidylinositoltriphosphate, ceramide phosphorylcholine, ceramidephosphorylethanolamine, ceramide phosphorylglycerol,dimyristoylphosphatidylcholine, di stearoylphosphatidylcholine,dilinoleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, or acombination of two or more thereof. In some embodiments, the carriercomprises one or more zwittterionic surfactants, wherein the one or morezwitterionic surfactants comprise lecithin.

Nonionic Surfactants

Suitable nonionic surfactants are categorized by theirhydrophilic-lipophilic balance (HLB) number, with a low value (<10)corresponding to greater lipophilicity and a higher value (>10)corresponding to higher hydrophilicity. Low HLB (<10) emulsifierinclude, without limitation, (a) alkylene glycol esters of fatty acidssuch as ethylene glycol esters of saturated and unsaturated C8-C24 fattyacids, propylene glycol esters of saturated and unsaturated C8-C24 fattyacids, butylene glycol esters of saturated and unsaturated C8-C24 fattyacids, high alkylene glycols of esters of saturated and unsaturatedC8-C24 fatty acids, and mixtures or combinations thereof, (b)unsaturated polyglycolized glycerides such as oleoyl macrogolglyceridesand linoleoyl macrogolglycerides, (c) sorbitan esters such as sorbitanmonooleate, sorbitan monostearate, sorbitan monolaurate, and sorbitanmonopalmitate; or (d) mixtures or combinations thereof. High HLB (>10)emulsifier include, without limitation, (a) polyoxyethylene sorbitanesters such as polysorbate 20, polysorbate 40, polysorbate 60, andpolysorbate 80; (b) polyoxyl castor oil derivatives such as Polyoxyl 35castor oil and Polyoxyl hydrogenated castor oil; (c) polyoxyethylenepolyoxypropylene block copolymer such as Poloxamer 188 and Poloxamer407; (d) saturated polyglycolized glycerides such as lauroylmacrogolglycerides and stearoyl macrogolglycerides; (e) PEG-8caprylic/capric glycerides such as caprylocaproyl macrogolglycerides;(f) vitamin E derivative such as tocopherol PEG succinate; or (g)mixtures or combinations thereof. Other suitable nonionic surfactantsinclude, without limitation, polyolesters, cyclic polyol esters,polyethylene glycol (PEG) esters, or mixtures and combination thereof.Exemplary examples include, without limitation, sorbitan monofattyand/or polyfatty acid esters, sorbitoal monofatty and/or polyfatty acidesters, mono fatty acid glycerides, polyethylene glycol (PEG) estersurfactants including hydrophilic and/or hydrophobic gelucires such ashydrophilic GELUCIRE® 44/14, lauroyl macrogol glyceride type 1500,hydrophobic GELUCIRE® 43/01, GELUCIRE® 39/01, GELUCIRE® 33/01, or othergelucires; polyglycol modified castor oils such as polyoxyl 35hydrogenated castor oil, polyoxyl hydrogenated castor oil; polyethyleneoxides; polypropylene oxides; poly(ethylene oxide and propylene oxide)polymers; polysorbates such as polysorbate 20, 40, 60, 80, etc., andTWEEN® surfactants; and mixtures or combinations thereof.

Exemplary examples of suitable nonionic surfactants include, withoutlimitation, SPAN® surfactants (available from Sigma-Aldrich) such asSPAN® 20—sorbitan laurate, sorbitan monolaurate, SPAN® 40—sorbitanmonopalmitate, SPAN® 60—sorbitan stearate, sorbitane monostearate, SPAN®80—sorbitane monooleate, sorbitan oleate, or other Span surfactants,TWEEN® surfactants such as TWEEN® 40—polyoxyethylene sorbitanmonopalmitate, TWEEN® 60—polyethylene glycol sorbitan monostearate,TWEEN® 80—polyoxyethylene-sorbitan-20 monooleate, POE (20) sorbitanmonooleate, polyethylene glycol sorbitan monooleate, polyoxyethylenesorbitan monooleate, polysorbate 80, BRIJ™ surfactants such as BRIJ™58—polyoxyethylene-20 hexadecyl ether, BRIJ™92-2-[(Z)-octadec-9-enoxy]ethanol, BRIJ™ 35—polyethoxylated laurylalcohol (yielding a lauryl ether), BRIJ™ 700—polyetholylated stearylalcohol, BRIJ™ 700—polyoxyethylene stearyl ether (HLB 18.8), or theother BRIJ™ surfactants, SOLULAN™C²⁴-2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanolor polyoxyethylene-24-cholesterol ether, PEG surfactants—polyethyleneoxides, TRITON™ surfactants such as TRITON™ X-100—octylphenol ethoxylatepolyoxyethylene 9.5-octlphenol, TRITON™X-80N—alkyl-oxy-polyethylene-oxy-polypropylene-oxyethanol, or otherTRITON™ surfactants, PLURONIC™ surfactants from Thermo Fisher, TERGITOL™surfactants from Dow Chemicals, SURFONIC™ JL-80X—alkoxylated linearalcohol, ETHOFAT™ 242/25—ethoxylated tall oil, alkyl polyglycoside,polyethylene glycol hexadecyl ether (CETOMACROGOL™ 1000), cetostearylalcohol, cetyl alcohol, cocamide DEA, cocamide MEA, decyl glucoside,decyl polyglucose, glycerol monostearate, IGEPAL®alkylphenoxypoly(ethyleneoxy)ethanols surfactants from Cameo such asIGEPAL® CA-630, ethoxylated iso-cetyl alcohol (Isoceteth-20), laurylglucoside or dodecyl β-d-glucopyranoside, maltoside or maltoseglycosides, Mycosubtilin, nonylphenoxypolyethoxyethanol (NONIDET™ P-40from Shell),26-(4-nonylphenoxy)-3,6,9,12,15,18,21,24-octaoxahexacosan-1-ol(Nonoxynol-9), nonaethylene glycol or polyethylene glycol nonyl phenylether (Nonoxynols), 4-nonylphenyl-polyethylene glycol (NP-40),octaethylene glycol monododecyl ether, N-octylbeta-d-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10sunflower glycerides, pentaethylene glycol monododecyl ether,ethoxylated dodecanol (Polidocanol), polyethoxylated tallow amine,polyglycerol polyricinoleate, stearyl alcohol, and mixtures orcombinations thereof. In some embodiments, one or more nonionicsurfactants comprise an ethylene glycol mono fatty acid ester, apropylene glycol mono fatty acid ester, or a combination of two or morethereof. In some embodiments, one or more nonionic surfactants compriseone or more selected from sorbitan mono-, di-, and tri-fatty acidesters. In some embodiments, one or more nonionic surfactants comprisesorbitan trioleate (STO), sorbitan monooleate, or sorbitan tristearate,or a combination thereof. In some embodiments, one or more nonionicsurfactants comprise propylene glycol monolaurate.

One or more nonionic surfactants may be present in the carrier in anamount of about wt. % to about 20 wt. %. This includes about 0.05, 0.06,0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0,1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.2, 5.4,5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2,8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, 10.0, 10.2, 10.4, 10.6, 10.8,11.0, 11.2, 11.4, 11.6, 11.8, 12.0, 12.2, 12.4, 12.6, 12.8, 13.0, 13.2,13.4, 13.6, 13.8, 14.0, 14.2, 14.4, 14.6, 14.8, 15.0, 15.2, 15.4, 15.6,16.0, 16.2, 16.4, 16.6, 16.8, 17.0, 17.2, 17.4, 17.6, 17.8, 18.0, 18.2,18.4, 18.6, 18.8, 19.0, 19.2, 19.4, 19.6, 19.8, or 20.0 wt. %, includingincrements thereof. In some embodiments, the one or more nonionicsurfactants are present in the carrier in an amount of about 0.05 wt. %to about 15 wt. %, about 0.05 wt. % to about 10 wt. %, about 0.05 wt. %to about 5 wt. %, about 0.05 wt. % to about 1 wt. %, about 0.1 wt. % toabout 20 wt. %, about 0.1 wt. % to about 15 wt. %, about wt. % to about10 wt. %, about 0.1 wt. % to about 5 wt. %, about 0.1 wt. % to about 1wt. %, about 0.5 wt. % to about 20 wt. %, about 0.5 wt. % to about 15wt. %, about 0.5 wt. % to about 10 wt. %, about 0.5 wt. % to about 5 wt.%, or about 0.5 wt. % to about 1 wt. %.

Sorbitan and Sorbitol Esters

Suitable sorbitan and/or sorbitol esters for use in this disclosureinclude, without limitation, sorbitan mono ester such as sorbitancaprylate, sorbitan undecylenate, sorbitan laurate, sorbitan palmitate,sorbitan isostearate, sorbitan oleate, sorbitan stearate, etc.; sorbitansesquiesters such as sesquicaprylate, sorbitan sesquiisostearate,sorbitan sesquioleate, sorbitan sesquistearate, etc.; sorbitan diesterssuch as sorbitan diisostearate, sorbitan dioleate, sorbitan distearate,etc.; sorbitan triesters such as sorbitan triisostearate, sorbitantrioleate, sorbitan tristearate, etc.; mixed-chain sorbitan esters suchas sorbitan cocoate, sorbitan olivate, sorbitan palmate, sorbitanTheobroma grandiflorum seedate, etc.; or mixtures and combinationsthereof. Other sorbitan or sorbitol esters include, without limitation,PEGs sorbitan and sorbitol fatty acid esters including PEG-20 sorbitancocoate, PEG-40 sorbitan diisostearate, PEG-2 sorbitan isostearate,PEG-5 sorbitan isosteatate, PEG-20 sorbitan isostearate, PEG-40 sorbitanlanolate, PEG-75 sorbitan lanolate, PEG-10 sorbitan laurate, PEG-40sorbitan laurate, PEG-44 sorbitan laurate, PEG-75 sorbitan laurate,PEG-80 sorbitan laurate, PEG-3 sorbitan oleate, PEG-6 sorbitan oleate,PEG-80 sorbitan palmitate, PEG-40 sorbitan perisostearate, PEG-40sorbitan peroleate, PEG-3 sorbitan stearate, PEG-6 sorbitan stearate,PEG-40 sorbitan stearate, PEG-60 sorbitan stearate, PEG-30 sorbitantetraoleate, PEG-40 sorbitan tetraoleate, PEG-60 sorbitan tetraoleate,PEG-60 sorbitan tetrasterate, PEG-160 sorbitan triisostearate; PEG-20sorbitan triisostearate, Sorbeth-40 hexaoleate, Sorbeth-50 hexaoleate,Sorbeth-30 tetraoleate laurate, Sorbeth-60 tetrastearate, and anymixture thereof. These PEG sorbitans or sorbitols range from tan, waxysolids and amber-colored pastes to clear yellow liquids. Other exemplarynonionic surfactants include, without limitation, polyoxyethylenesurfactants such as POE sorbitan monolaurate (TWEEN® 20, HLB 17), POEsorbitan monopalmitate (TWEEN® 40, HLB 15.6), POE sorbitan monostearate(TWEEN® 60, HLB 15.0), POE sorbitan monooleate (TWEEN® 80, HLB 15.0),POE sorbitan tristearate (TWEEN® 65, HLB 10.5), POE sorbitan trioleate(TWEEN® 85, HLB 11.0), POE glycerol trioleate (TAGAT® TO, HLB 11.5),POE-40-hydrogenated castor oil (solid) Cremophor RH 40, HLB 14.0 to16.0), POE-35-castor oil (Cremophor EL (liquid), HLB 12.0-14.0), POE(10) oleyl ether (BRIJ® 96, HLB 12.4), POE (23) lauryl ether (BRIJ® 35,HLB 16.9), POE-vitamin E (Alpha-tocopherol TPGS, HLB 13.0), and mixturesor combinations thereof.

Poloxamers

Suitable poloxamers include, without limitation, are nonionic triblockcopolymers composed of a central hydrophobic chain of polyoxypropylene(poly(propylene oxide)) flanked by two hydrophilic chains ofpolyoxyethylene (poly(ethylene oxide)). Poloxamers are also known by thetradenames SYNPERONIC®, PLURONIC®, and KOLLIPHOR®. Because the lengthsof the polymer blocks can be customized, many different poloxamers existthat have slightly different properties. For the generic term poloxamer,these copolymers are commonly named with the letter P (for poloxamer)followed by three digits: the first two digits multiplied by 100 givethe approximate molecular mass of the polyoxypropylene core, and thelast digit multiplied by 10 gives the percentage polyoxyethylene content(e.g., P407=poloxamer with a polyoxypropylene molecular mass of 4000g/mol and a 70% polyoxyethylene content). For the PLURONIC® andSYNPERONIC® tradenames, coding of these copolymers starts with a letterto define its physical form at room temperature (L=liquid, P=paste,F=flake (solid)) followed by two or three digits, The first digit (twodigits in a three-digit number) in the numerical designation, multipliedby 300, indicates the approximate molecular weight of the hydrophobe;and the last digit x 10 gives the percentage polyoxyethylene content(e.g., L61 indicates a polyoxypropylene molecular mass of 1800 g/mol anda 10% polyoxyethylene content). In the example given, poloxamer 181(P181)=PLURONIC® L61 and SYNPERONIC® PE/L 61.

Nonionic Neutral Polymers

Suitable nonionic neutral polymers include, without limitation, pHresponsive nonionic polymers and temperature sensitive nonionicpolymers. Exemplary examples of such pH responsive nonionic polymersinclude, without limitation, pH responsive dendrimers such aspoly-amidoamide (PAMAM), dendrimers, poly(propyleneimine) dendrimers,poly(l-lisine) ester, poly(hydroxyproline), Poly(propyl acrylic acid),poly(methacrylic acid), CARBOPOL®, EUDRAGIT® S-100, EUDRAGIT® L-100,chitosan, poly(methacrylic acid) (PMMA), PMAA-PEG copolymer,N,N-dimethylaminoethyl methacrylate (DMAEMA), and any mixture thereof.Exemplary examples of temperature sensitive polymer include, withoutlimitation, poloxamers, prolastin, poly(n-substituted acrylamide),poly(organophosphazene), cyclotriphosphazenes with poly(ethyleneglycol)and amino acid esters, block copolymers of poly(ethyleneglycol)/poly(lactic-co-glycolic acid), poly(ethylene glycol) (PEG),poly(propylene glycol) (PPG), PMAA, poly(vinyl alcohol) (PVA), varioussilk-elastin-like polymers, poly(silamine), poly(vinyl methyl ether)(PVME), poly(vinyl methyl oxazolidone) (PVMO), poly(vinyl pyrrolidone)(PVP), poly(n-vinylcaprolactam), poly(N-vinyl isobutyl amid), poly(vinylmethyl ether), poly(N-vinylcaprolactam) (PVCL), poly(siloxyethyleneglycol), poly(dimethylamino ethyl methacrylate), triblock copolymerpoly(DL-lactide-co-glycolide-b-ethyleneglycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA), cellulosederivatives, alginate, gellan, xyloglucan, and any mixture thereof.

Neutral Lipids

Fatty Acid Esters

In some embodiments, a neutral lipid disclosed herein comprise at leastone fatty acid ester. Fatty acid esters comprise esters of any of thefatty acids listed above including, without limitation, mono-alcoholesters, where the mono-alcohol or polyols including 1 carbon atom to 20carbon atoms, where one or more of the carbon atoms may be replace by O,NR (R is a hydrocarbyl group having between 1 and 5 carbon atoms), or S.Exemplary mono-alcohols used to from the free fatty acid esters includemethanol, ethanol, propanol, butanol, pentanol or mixtures thereof.

Biocompatible Oils

Suitable biocompatible oils include, without limitation, any oilapproved for a human, mammal or animal consumption by the FDA or othergovernmental agency. Exemplary biocompatible oils include, withoutlimitation, plant derived oils or animal derived oils or theirderivatives or synthetic oils. In certain embodiments, the natural oilsare oils rich in phospholipids such as lecithin oils from soybeans.Exemplary examples of plant derived oils or animal derived oils or theirderivatives or synthetic oils include, without limitation, essentialoils, vegetable oils an hydrogenated vegetable oils such as peanut oil,canola oil, avocado oil, safflower oil, olive oil, corn oil, soy beanoil, sesame oil, vitamin A, vitamin D, vitamin E, or the like, animaloils, fish oils, krill oil, or the like or mixture thereof.

In certain embodiments, the biocompatible oil includes a neutral lipid.Suitable neutral lipids include, without limitation, any neutral lipidsuch as the fatty acid esters, monoglyceride, diglyceride, and/ortriglyceride. For a partial listing of representative neutral lipids,such as the triglycerides, reference is specifically made to U.S. Pat.Nos. 4,950,656 and 5,043,329, incorporated by reference herein. Bothsaturated and unsaturated triglycerides may be employed in the presentcompositions, and include such triglycerides as tripalmitin (saturated),triolein and trilinolein (unsaturated). However, these particulartriglycerides are listed here for convenience only, and are merelyrepresentative of a variety of useful triglycerides and is further notintended to be inclusive.

Animal fats include, without limitation, lard, duck fat, butter, ormixture or combination thereof.

Vegetable fats include, without limitation, coconut oil, palm oil,cottonseed oil, wheat germ oil, soya oil, olive oil, corn oil, sunfloweroil, safflower oil, hemp oil, canola/rapeseed oil, or mixture andcombinations thereof.

One or more neutral lipids may be present in the carrier in an amount ofabout 30 wt. % to about 75 wt. %. This includes about 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, or 75 wt. %, including increments therein. In someembodiments, the one or more neutral lipids may be present in thecarrier in an amount of about 30 wt. % to about 70 wt. %, about 30 wt. %to about 60 wt. %, about 30 wt. % to about 55 wt. %, about 35 wt. % toabout 75 wt. %, about 35 wt. % to about 70 wt. %, about 35 wt. % toabout 65 wt. %, about 35 wt. % to about 60 wt. %, about 35 wt. % toabout 55 wt. %, about 40 wt. % to about 75 wt. %, about 40 wt. % toabout 70 wt. %, about 40 wt. % to about 65 wt. %, about 40 wt. % toabout 60 wt. %, or about 40 wt. % to about 55 wt. %.

In some embodiments, the carrier comprises one or more neutral lipids,wherein the one or more neutral lipids comprise a fatty acid ester. Insome embodiments, the fatty acid ester is a fatty acid methyl ester. Insome embodiments, the fatty acid methyl ester is methyl linolenate,methyl oleate, or methyl palmitate, or a combination of thereof.

V. Excipients or Adjuvants

The formulation or compositions of this disclosure can also includeother chemicals, such as anti-oxidants (e.g., Vitamin A, C, D, E, etc.),trace metals and/or polyvalent cations (aluminum, gold, copper, zinc,calcium, etc.), surface-active agents and/or solvents (e.g., propyleneglycol/PPG, dimethyl sulfoxide/DMSO, medium chain triglycerides/MCT,etc.), non-toxic dyes and flavor enhancers may be added to theformulation as they are being prepared to improve stability,fluidity/spreadability, permeability, effectiveness and consumeracceptance. These additives, excipients, and/or adjuvants may alsofunction as active agents.

VI. BAI and Pharmaceutical Agents

Suitable pharmaceutical agents for use in the compositions of thisdisclosure include, without limitation, any pharmaceutical agent capableof being dispersed in a carrier of this disclosure. In certainembodiments, the pharmaceutical agents are solids. In other embodiments,the pharmaceutical agents are liquids. In other embodiments, thepharmaceutical agents are weak acid pharmaceutical agents. In otherembodiments, the pharmaceutical agents are weak base pharmaceuticalagents. In some embodiments, the biologically active agent comprises atleast one agent selected from the group consisting of an acid-labilepharmaceutical agent, an anti-depressant, an anti-diabetic agent, ananti-epileptic agent, an anti-fungal agent, an anti-malarial agent, ananti-muscarinic agent, an anti-neoplastic agent, an immunosuppressant,an anti-protozoal agent, an anti-tussive, a neuroleptics, abeta-blocker, a cardiac inotropic agent, a corticosteroid, ananti-parkinsonian agent, a gastrointestinal agent, histamine, ahistamine receptor antagonist, a keratolytic, a lipid regulating agent,a muscle relaxant, a nitrate, an anti-anginal agent, a non-steroidalanti-inflammatory agent, a nutritional agent, an opioid analgesic, a sexhormone, a stimulant, a nutraceutical, a peptide, a protein, atherapeutic protein, a nucleoside, a nucleotide, DNA, RNA, aglycosaminoglycan, an acid-labile drug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amideranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.

Hydrophobic Pharmaceutical and/or Nutraceutical Agents

Hydrophobic therapeutic agents suitable for use in the pharmaceuticalcompositions of the present disclosure are not particularly limited, asthe carrier is surprisingly capable of solubilizing and delivering awide variety of hydrophobic therapeutic agents. Hydrophobic therapeuticagents are compounds with little or no water solubility. Intrinsic watersolubilities (i.e., water solubility of the unionized form) forhydrophobic therapeutic agents usable in the present disclosure are lessthan about 1% by weight, and typically less than about 0.1% or 0.01% byweight. Such therapeutic agents can be any agents having therapeutic orother value when administered to an animal, particularly to a mammal,such as drugs, nutrients, and cosmetics (cosmeceuticals). It should beunderstood that while the disclosure is described with particularreference to its value in the form of aqueous dispersions, thedisclosure is not so limited. Thus, hydrophobic drugs, nutrients orcosmetics which derive their therapeutic or other value from, forexample, topical or transdermal administration, are still considered tobe suitable for use in the present disclosure.

Specific non-limiting examples of hydrophobic therapeutic agents thatcan be used in the pharmaceutical compositions of the present disclosureinclude the following representative compounds, as well as theirpharmaceutically acceptable salts, isomers, esters, ethers and otherderivatives: analgesics and anti-inflammatory agents, such as aloxiprin,auranofin, azapropazone, benorylate, capsaicin, celecoxib, diclofenac,diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, leflunomide,meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,oxyphenbutazone, phenylbutazone, piroxicam, refocoxib, sulindac,tetrahydrocannabinol, tramadol and tromethamine; antihelminthics, suchas albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen,ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate,praziquantel, pyrantel embonate and thiabendazole; anti-arrhythmicagents, such as amiodarone HCl, disopyramide, flecainide acetate andquinidine sulfate; anti-asthma agents, such as zileuton, zafirlukast,terbutaline sulfate, montelukast, and albuterol; anti-bacterial agentssuch as alatrofloxacin, azithromycin, baclofen, benzathine penicillin,cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin,demeclocycline, dirithromycin, doxycycline, erythromycin, ethionamide,furazolidone, grepafloxacin, imipenem, levofloxacin, lorefloxacin,moxifloxacin HCl, nalidixic acid, nitrofurantoin, norfloxacin,ofloxacin, rifampicin, rifabutine, rifapentine, sparfloxacin,spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, trimethoprim, trovafloxacin, andvancomycin; anti-viral agents, such as abacavir, amprenavir,delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine,ritonavir, saquinavir, and stavudine; anti-coagulants, such ascilostazol, clopidogrel, dicumarol, dipyridamole, nicoumalone,oprelvekin, phenindione, ticlopidine, and tirofiban; anti-depressants,such as amoxapine, bupropion, citalopram, clomipramine, fluoxetine HCl,maprotiline HCl, mianserin HCl, nortriptyline HCl, paroxetine HCl,sertraline HCl, trazodone HCl, trimipramine maleate, and venlafaxineHCl; anti-diabetics, such as acetohexamide, chlorpropamide,glibenclamide, gliclazide, glipizide, glimepiride, miglitol,pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide andtroglitazone; anti-epileptics, such as beclamide, carbamazepine,clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine,methoin, methsuximide, methylphenobarbitone, oxcarbazepine,paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide,primidone, sulthiame, tiagabine HCl, topiramate, valproic acid, andvigabatrin; anti-fungal agents, such as amphotericin, butenafine HCl,butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole,natamycin, nystatin, sulconazole nitrate, oxiconazole, terbinafine HCl,terconazole, tioconazole and undecenoic acid; anti-gout agents, such asallopurinol, probenecid and sulphinpyrazone; anti-hypertensive agents,such as amlodipine, benidipine, benezepril, candesartan, captopril,darodipine, dilitazem HCl, diazoxide, doxazosin HCl, elanapril,eposartan, losartan mesylate, felodipine, fenoldopam, fosenopril,guanabenz acetate, irbesartan, isradipine, lisinopril, minoxidil,nicardipine HCl, nifedipine, nimodipine, nisoldipine, phenoxybenzamineHCl, prazosin HCl, quinapril, reserpine, terazosin HCl, telmisartan, andvalsartan; anti-malarials, such as amodiaquine, chloroquine,chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl,pyrimethamine and quinine sulfate; anti-migraine agents, such asdihydroergotamine mesylate, ergotamine tartrate, frovatriptan,methysergide maleate, naratriptan HCl, pizotyline malate, rizatriptanbenzoate, sumatriptan succinate, and zolmitriptan; anti-muscarinicagents, such as atropine, benzhexol HCl, biperiden, ethopropazine HCl,hyoscyamine, mepenzolate bromide, oxyphencyclimine HCl and tropicamide;anti-neoplastic agents and immunosuppressants, such asaminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene,busulfan, camptothecin, cytarabine, chlorambucil, cyclosporin,dacarbazine, ellipticine, estramustine, etoposide, irinotecan,lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel,procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate, teniposide,testolactone, topotecan HCl, and toremifene citrate; antiprotozoalagents, such as atovaquone, benznidazole, clioquinol, decoquinate,diiodohydroxyquinoline, diloxanide furoate, dinitolmide, furazolidone,metronidazole, nimorazole, nitrofurazone, ornidazole and tinidazole;anti-thyroid agents, such as carbimazole, paracalcitol, andpropylthiouracil; anti-tussives, such as benzonatate; anxiolytics,sedatives, hypnotics and neuroleptics, such as alprazolam,amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam,clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,triflupromazine, fluphenthixol decanoate, fluphenazine decanoate,flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam,meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam,molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone,perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine,rispiridone, sertindole, sulpiride, temazepam, thioridazine, triazolam,zolpidem, and zopiclone; .beta.-Blockers, such as acebutolol,alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol,pindolol and propranolol; cardiac inotropic agents, such as amrinone,digitoxin, digoxin, enoximone, lanatoside C and medigoxin;corticosteroids, such as beclomethasone, betamethasone, budesonide,cortisone acetate, desoxymethasone, dexamethasone, fludrocortisoneacetate, flunisolide, fluocortolone, fluticasone propionate,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone; diuretics, such as acetazolamide, amiloride,bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone,ethacrynic acid, frusemide, metolazone, spironolactone and triamterene.antiparkinsonian agents, such as bromocriptine mesylate, lysuridemaleate, pramipexole, ropinirole HCl, and tolcapone; gastrointestinalagents, such as bisacodyl, cimetidine, cisapride, diphenoxylate HCl,domperidone, famotidine, lansoprazole, loperamide, mesalazine,nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium, ranitidineHCl and sulphasalazine; histamine H, and H,-receptor antagonists, suchas acrivastine, astemizole, chlorpheniramine, cinnarizine, cetrizine,clemastine fumarate, cyclizine, cyproheptadine HCl, dexchlorpheniramine,dimenhydrinate, fexofenadine, flunarizine HCl, loratadine, meclizineHCl, oxatomide, and terfenadine; keratolytics, such as such asacetretin, calcipotriene, calcifediol, calcitriol, cholecalciferol,ergocalciferol, etretinate, retinoids, targretin, and tazarotene; lipidregulating agents, such as atorvastatin, bezafibrate, cerivastatin,ciprofibrate, clofibrate, fenofibrate, fluvastatin, gemfibrozil,pravastatin, probucol, and simvastatin; muscle relaxants, such asdantrolene sodium and tizanidine HCl; nitrates and other anti-anginalagents, such as amyl nitrate, glyceryl trinitrate, isosorbide dinitrate,isosorbide mononitrate and pentaerythritol tetranitrate; nutritionalagents, such as calcitriol, carotenes, dihydrotachysterol, essentialfatty acids, nonessential fatty acids, phytonadiol, vitamin A, vitaminB2, vitamin D, vitamin E and vitamin K. opioid analgesics, such ascodeine, codeine, dextropropoxyphene, diamorphine, dihydrocodeine,fentanyl, meptazinol, methadone, morphine, nalbuphine and pentazocine;sex hormones, such as clomiphene citrate, cortisone acetate, danazol,dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone,fluoxymesterone, medroxyprogesterone acetate, megestrol acetate,mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol,conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol,testosterone and tibolone; stimulants, such as amphetamine,dexamphetamine, dexfenfluramine, fenfluramine and mazindol; and others,such as becaplermin, donepezil HCl, L-thryroxine, methoxsalen,verteporfrin, physostigmine, pyridostigmine, raloxifene HCl, sibutramineHCl, sildenafil citrate, tacrine, tamsulosin HCl, and tolterodine.

Exemplary examples of hydrophobic therapeutic agents include sildenafilcitrate, amlodipine, tramadol, celecoxib, rofecoxib, oxaprozin,nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast,cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine,loratadine, famotidine, paricalcitol, atovaquone, nabumetone,tetrahydrocannabinol, megestrol acetate, repaglinide, progesterone,rimexolone, cyclosporin, tacrolimus, sirolimus, teniposide, paclitaxel,pseudoephedrine, troglitazone, rosiglitazone, finasteride, vitamin A,vitamin D, vitamin E, and pharmaceutically acceptable salts, isomers andderivatives thereof. Particularly preferred hydrophobic therapeuticagents are progesterone and cyclosporin.

Suitable proton pump inhibitors for use in the present disclosureinclude, without limitation, omeprazole, lansoprazole, rabeprazole,pantoprazole, esomeprazole, and mixtures thereof.

It should be appreciated that this listing of hydrophobic therapeuticagents and their therapeutic classes is merely illustrative. Indeed, aparticular feature and surprising advantage, of the compositions of thepresent disclosure is the ability of the present compositions tosolubilize and deliver a broad range of hydrophobic therapeutic agents,regardless of functional class. Of course, mixtures of hydrophobictherapeutic agents may also be used where desired. These carrierattributes will also be equally effective as a delivery vehicle for yetto be developed hydrophobic therapeutic agents.

In certain embodiments, the suitable pharmaceutical agents for use inthe compositions of this disclosure include, without limitation, weakacid pharmaceuticals, weak acid pharmaceuticals or mixtures andcombinations thereof. Exemplary weak acid pharmaceuticals include,without limitation, anti-inflammatory pharmaceuticals, steroids,sterols, NSAID, COX-2 inhibitors, or mixture thereof. Exemplary weakbase pharmaceuticals include, without limitation, weak base antibiotics,caffeine, codiene, ephedrine, chlordiazepoxide, morphine, pilocarpine,quinine, tolbutamine, other weak base pharmaceutical agents and mixturesor combinations thereof. Exemplary anti-inflammatory pharmaceuticalsinclude steroidal anti-inflammatory drugs, nonsteroidalanti-inflammatory drugs, acetaminophen and COX-2 inhibitors or mixturesand combinations thereof.

Suitable NSAIDS include, without limitation: (a) propionic acid drugsincluding fenoprofen calcium, flurbiprofen, suprofen, benoxaprofen,ibuprofen, ketoprofen, naproxen, and/or oxaprozin; (b) acetic acid drugincluding diclofenac sodium, diclofenac potassium, aceclofenac,etodolac, indomethacin, ketorolac tromethamine, and/or ketorolac; (c)ketone drugs including nabumetone, sulindac, and/or tolmetin sodium; (d)fenamate drugs including meclofenamate sodium, and/or mefenamic acid;(e) oxicam drugs piroxicam, lornoxicam and meloxicam; (f) salicylic aciddrugs including diflunisal, aspirin, magnesium salicylate, bismuthsubsalicylate, and/or other salicylate pharmaceutical agents; (g)pyrazolin acid drugs including oxyphenbutazone, and/or phenylbutazone;and (h) mixtures or combinations thereof.

Suitable COX-2 inhibitors include, without limitation, celecoxib,rofecoxib, or mixtures and combinations thereof.

Acid Labile Pharmaceuticals

Suitable acid labile pharmaceutical active agents include, withoutlimitation, peptides, proteins, nucleosides, nucleotides, DNA, RNA,glycosaminoglyacan, any other acid labile pharmaceuticals, or mixturesor combinations thereof. Examples of acid-labile drugs which may be usedin the carrier systems disclosed herein are, e.g.,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, hormones (in particular estrogens,insulin, adrenalin and heparin), lipase, milameline, novobiocin,pancreatin, penicillin salts, polymyxin, pravastatin, progabide,protease, quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]amide,ranitidine, streptomycin, subtilin, sulphanilamide and acid-labileproton pump inhibitors like esomeprazole, lansoprazole, minoprazole,omeprazole, pantoprazole or rabeprazole. Digestive proteins such asamylase, lipase and protease may be included in disclosed carriersystems. Amylases, lipases and proteases which are suitable as digestiveenzyme supplement or digestive enzyme substitute in mammals,particularly humans, are preferred. Amylase, lipase and/or protease maybe derived from microbial or animal, in particular, mammalian sources.Pancreatin is an acid-labile drug. Other therapeutic proteins orpeptides may be used with the disclosed carriers to increasebioavailability. Other therapeutic proteins may include, withoutlimitation, insulin, erythropoietin, or fragments or derivativesthereof. Example of glycosaminoglycan include, without limitation,heparin, or fragments thereof. The foregoing list of acid-labile drugsis not meant to be exhaustive, but merely illustrative as a person ofordinary skill in the art would understand that many other acid-labiledrugs or combination of acid-labile drugs could also be used.

Nutraceutical Agents

Suitable nutraceuticals for use in the compositions of this disclosureinclude, without limitation, any nutraceutical agent that is capablewith the carriers of this disclosure. In certain embodiments, thenutraceutical agents are solid. In other embodiments, the nutraceuticalagents are oil soluble liquids or oil miscible liquids.

Additionally, or alternatively, suitable pharmaceutical agents for usein the compositions of this disclosure may be categorized as class I,II, III, or IV pharmaceuticals, defined as follows.

Class I pharmaceuticals are characterized in that the API has a higherconcentration in oil phases in the initial pH 1 solution and final pH 1solution compared to the concentration of the API in oil phase in the pH7 solution. Class I pharmaceuticals are small molecule pharmaceuticalscharacterized in that the pharmaceuticals do not include functionalgroups that protonate at pH less than about 2 or 3; such groups includeprimary, secondary and tertiary amines, guanidines, pyridines,imidazole, benzimidazole, histidine, phosphazene, similar or mixturesand combinations thereof. Class I pharmaceuticals may include linear,branched, cyclic, saturated and/or unsaturated alkyl groups, aralkylgroups, aralkyl groups, aryl groups, hydroxy groups, alkoxy groups,carbonyl group, carboxylic acid groups, carboxylic ester groups, acetategroups, amide groups, sulfone groups, sulfonamide groups, cyclic rings,or heterocyclic groups that do not protonate at pH less than about 2 or3, or mixtures and combinations thereof. Exemplary examples of class Ipharmaceutical include, 5-alpha-reductase inhibitors, ACE inhibitorswith calcium channel blocking agents, aldosterone receptor antagonists,adrenal cortical steroids, group V anti-arrhythmics, fatty acidderivative anti-convulsants, fibric acid derivatives, mitoticinhibitors, MTOR inhibitors, NSAIDs (such as ibuprofen and aspirin),COX-2 inhibitors, otic steroids, sterols, steroids, transthyretinstabilizers, uterotonic agents, vasopressin antagonists, or mixtures andcombination thereof.

Class II pharmaceuticals are characterized in that the API has lowerconcentration in oil phases in the initial pH 1 solution and final pH 1solution compared to the concentration of the API in oil phase in the pH7 solution. Class II pharmaceuticals are small molecule pharmaceuticalscharacterized in that the pharmaceuticals include functional groups thatprotonate at pH less than about 3 or less than about 2; functionalgroups include primary, secondary and tertiary amines, guanidines,pyridines, imidazole, benzimidazole, histidine, phosphazene, similar ormixtures and combinations thereof. Exemplary examples of class IIpharmaceuticals include proton-pump inhibitors (such as omeprazole), ormixtures and combination thereof.

Class III pharmaceuticals are characterized in that the API has a higherconcentration in oil phases in the initial pH 1 solution and final pH 1solution compared to the concentration of the API in oil phase in the pH7 solution. Exemplary examples of class III pharmaceuticals includeproteins, polypeptides, enzymes, ribozymes, RNA, DNA, or mixtures andcombination thereof.

Class IV pharmaceuticals are characterized in that the API has lowerconcentration in oil phases in the initial pH 1 solution and final pH 1solution compared to the concentration of the API in oil phase in the pH7 solution. This class may include carbohydrates, polysaccharides, otherhighly water soluble macromolecules.

VII. Pharmaceutical or Nutraceutical Dosages

In pharmaceutical compositions, the compositions generally contain fromabout 1 mg to about 5000 mg per dose depending on the pharmaceuticalagent(s). In other pharmaceutical compositions, the compositions containfrom about 10 mg to about 2500 mg per dose depending on thepharmaceutical agent(s). In other pharmaceutical compositions, thecompositions contain from about 250 mg to about 2500 mg per dosedepending on the pharmaceutical agent(s). In other pharmaceuticalcompositions, the compositions contain from about 500 mg to about 2500mg per dose depending on the pharmaceutical agent(s). In otherpharmaceutical compositions, the compositions contain from about 500 mgto about 2000 mg per dose depending on the pharmaceutical agent(s). Inother pharmaceutical compositions, the compositions contain from about 1mg to about 2000 mg per dose depending on the pharmaceutical agent(s).In other pharmaceutical compositions, the compositions contain fromabout 1 mg to about 1000 mg per dose depending on the pharmaceuticalagent(s). Of course, the exact dosage for each composition depends onthe pharmaceutical agent(s) used and the potency of the pharmaceuticalagent(s).

In nutraceutical compositions, the compositions generally contain fromabout 1 mg to about 5000 mg per dose depending on the nutraceuticalagent(s). In other nutraceutical compositions, the compositions containfrom about 10 mg to about 2500 mg per dose depending on thenutraceutical agent(s). In other nutraceutical compositions, thecompositions contain from about 250 mg to about 2500 mg per dosedepending on the nutraceutical agent(s). In other nutraceuticalcompositions, the compositions contain from about 500 mg to about 2500mg per dose depending on the nutraceutical agent(s). In othernutraceutical compositions, the compositions contain from about 500 mgto about 2000 mg per dose depending on the nutraceutical agent(s). Inother nutraceutical compositions, the compositions contain from about 1mg to about 2000 mg per dose depending on the nutraceutical agent(s). Inother nutraceutical compositions, the compositions contain from about 1mg to about 1000 mg per dose depending on the nutraceutical agent(s). Ofcourse, the exact dosage for each composition depends on thepharmaceutical agent(s) used and the potency of the pharmaceuticalagent(s).

VIII. Methods for Making the Carriers and Compositions

Some embodiments of the present disclosure relate broadly to methods formaking the carriers of this disclosure including contacting (1) a pHdependent release system and (2) a pH dependent carrierreassembly/assembly and reabsorption/absorption system under conditionsof mixing, temperature, pressure, and time sufficient to form a carrierhaving tailored properties. The pH dependent release system is capableof targeting the release of one or more biologically active agents at adesired pH and the pH dependent carrier reassembly/assembly andreabsorption/absorption system is capable of reforming or forming acarrier due to duodenal reflux and a reabsorption/absorption of thebiologically active agents in the low pH environment of the stomach. Incertain embodiments, the mixing contacting occur in the presence of asolvent followed by solvent removal so that the resulting carrier issubstantially free of solvent.

In certain embodiments, the methods for making the carriers of thisdisclosure including contacting (1) pH dependent release system, (2) apH dependent carrier reassembly/assembly and biologically active agentreabsorption/absorption due to duodenal reflux, (3) optionally one ormore neutral lipids, (4) optionally one or more surfactants, (5)optionally a biologically active agent complexing agent, and (6)optionally a protective system including agents to reduce and/oreliminate biologically active agent toxicities, irritations orside-effects. The carriers are generally viscous fluids capable of beingorally administered, directly administered, internally administeredand/or topically administered. Again, in certain embodiments, the mixingcontacting occur in the presence of a solvent followed by solventremoval so that the resulting carrier is substantially free of solvent.

In other embodiments, the carriers are generally prepared at roomtemperature, at atmospheric pressure with mixing for a time sufficientto render the carrier uniform and/or homogeneous or substantiallyuniform and/or substantially homogeneous. However, the carrier may beprepared and higher or lower pressures. In other embodiments, the mixingmay be performed at an elevated temperature up to a melting point of thehighest melting component, but below a decomposition temperature of anyof the carrier components. In other embodiments, the temperature iselevated to a temperature up to about 130° C. In other embodiments, thetemperature is elevated to a temperature up to about 80° C. In otherembodiments, the temperature is elevated to a temperature up to about60° C. In other embodiments, the temperature is elevated to atemperature up to about 40° C.

In other embodiments, the pressure at or near atmospheric pressure. Inother embodiments, the pressure is above atmospheric pressure. In otherembodiments, the pressure is below atmospheric pressure.

In other embodiments, the time is for a period between about 5 minutesand about 12 hours. In other embodiments, the time is for a periodbetween about 10 minutes and about 8 hours. In other embodiments, thetime is for a period between about 20 minutes and about 4 hours. Inother embodiments, the time is for a period between about 30 minutes andabout 2 hours. In other embodiments, the time is for a period betweenabout 30 minutes and about 1 hour.

In other embodiments, the mixing is performed by low shear mixing suchas paddle mixers. In other embodiments, the mixing is performed by highshear mixing such as extruders, internal mixers, etc. In certainembodiments, the mixing is performed by a combination of low shearmixing and high shear mixing. In certain embodiments, the mixing isperformed by sonication with or without low shear and/or high shearmixing. In certain embodiments, the mixing is performed by vortex mixingin the presence or absence of sonication.

In other embodiments, the present disclosure relates broadly to methodsfor making the compositions of this disclosure by contacting a carrierof this disclosure and an effective amount of at least one biologicallyactive agent under conditions of mixing, temperature, pressure and timesufficient to form a composition having tailored properties, wherein thecarrier includes (1) pH dependent release system, (2) a pH dependentcarrier reassembly/assembly and biologically active agentreabsorption/absorption due to duodenal reflux, (3) optionally one ormore neutral lipids, (4) optionally one or more surfactants, (5)optionally a biologically active agent complexing agent, and (6)optionally a protective system including agents to reduce and/oreliminate biologically active agent toxicities, irritations orside-effects. In certain embodiments, the compositions may also includea secondary complexing agent for the active agent under conditions ofmixing, temperature, pressure, and time sufficient to form a compositionhaving tailored properties in the presence or absence of a solventsystem. If solvent system is used, then the system is generally removedprior to use. In certain embodiments, the compositions may also includea protective agent for the active agents. In certain embodiments, theactive agents include pharmaceutical agents, nutraceutical agent ormixtures and combinations thereof. In certain embodiments, thecompositions are made at room temperature, at atmospheric pressure withmixing until the carrier is uniform and/or homogeneous. In otherembodiments, the mixing may be performed at an elevated temperature upto a melting point of the highest melting component, but below adecomposition temperature of any of the carrier components. In otherembodiments, the temperature is elevated to a temperature up to about130° C. In other embodiments, the temperature is elevated to atemperature up to about 80° C. In other embodiments, the temperature iselevated to a temperature up to about 60° C. In other embodiments, thetemperature is elevated to a temperature up to about 40° C. In certainembodiments, the pressure at or near atmospheric pressure. In otherembodiments, the pressure is above atmospheric pressure. In otherembodiments, the pressure is below atmospheric pressure.

In certain embodiments, the mixture is mixed for a time between about 5minutes and about 12 hours. In other embodiments, the time is for aperiod between about 10 minutes and about 8 hours. In other embodiments,the time is for a period between about 20 minutes and about 4 hours. Inother embodiments, the time is for a period between about 30 minutes andabout 2 hours. In other embodiments, the time is for a period betweenabout 30 minutes and about 1 hour.

In certain embodiments, the mixing is performed by low shear mixing suchas paddle mixers. In other embodiments, the mixing is performed by highshear mixing such as extruders, internal mixers, etc. In certainembodiments, the mixing is performed by a combination of low shearmixing and high shear mixing. In certain embodiments, the mixing isperformed by sonication with or without low shear and/or high shearmixing. In certain embodiments, the mixing is performed by vortex mixingin the presence or absence of sonication. Of course, the compositionsmay be prepared by mixing the active agents and the carrier componentsin any order, thus, the carrier does not have to be pre-made prior toadding the active agents. Additionally, the order of addition is notcritical and may vary depending on components, mixers, desired finalproperties, or operator choice.

IX. Methods for Using the Carriers and Compositions

Some embodiments of the present disclosure broadly relate to methods oftargeting release of a biologically active agent at specific portion ofa tract such as the gastrointestinal (GI) tract, wherein the methodscomprise the step of orally administering a composition comprising acarrier and at least one biologically active agent. The carrier includesan effective amount of a pH dependent release system and an effectiveamount of a pH dependent carrier assembly or reassembly system. The pHdependent release system is designed to release the at least onebiologically active agent in pH sensitive manner characterized in thatless than 20% of the at least one biologically active agent is releasedinto gastric fluid and greater than 50% of the at least one biologicallyactive agent is released in intestinal fluid having a pH value greaterthan pH 3. In certain embodiments, pH dependent release system includescompounds that are uncharged in gastric fluid and charged in intestinalfluids, which is responsible for the pH dependent release of the atleast one biologically active agent.

Some embodiments of the present disclosure relate broadly to methods forusing the compositions of this disclosure by administering a compositionof this disclosure to a human, a mammal or an animal at a dosesufficient to illicit at least one therapeutic effect such as treatmentand/or prevention of pain, fever, inflammation, cancer, inflammatorybowel syndrome, crones disease, cardiovascular disease, infections,brain and spinal cord injury, Alzheimer's disease, other neurologicdiseases diabetes, and/or any other disease or malady treatable via theadministration of an active agent such as a pharmaceutical and/ornutraceutical agents. In other embodiments, the compositions treat,prevent and/or ameliorate symptoms of diseases and/or maladies.

Some embodiments of the present disclosure relate broadly to methodsincluding orally or internally administering a composition including acarrier of this disclosure and a therapeutically effective amount of acomposition of this disclosure to increase transport of thepharmaceutical or nutraceutical agent across the blood-brain barrier orinto the central nervous system (CNS) or peripheral nervous system (PNS)allowing more pharmaceutical or nutraceutical agent to get to the traumasite and reduce inflammation, platelet aggregation, pain (nociceptive)sensation, cell death and/or apoptosis due to inflammation and/orinducing competitive cell death of cancer cells in preventing ortreating cancers.

Some embodiments of the present disclosure relate broadly to methodsincluding orally or internally administering a composition including acarrier of this disclosure and a therapeutically effective amount of acomposition of this disclosure to prevent, treat and/or amelioratesymptoms associated with Alzheimer's disease.

Some embodiments of the present disclosure relate broadly to methodsincluding administering a composition of this disclosure to a human,mammal or animal. The carriers may be tailored so that the compositionshave good pharmaceutical and/or nutraceutical release characteristics,have reduced pharmaceutical and/or nutraceutical toxicity or irritation,have increased pharmaceutical and/or nutraceutical bioavailability andhave increased pharmaceutical or nutraceutical availability acrossrelatively hydrophobic barriers in a human, mammal or animal. Forexample, pharmaceuticals and/or nutraceuticals that have GI toxicityand/or GI irritation, the carriers of this disclosure may be tailored toameliorate, reduce, or eliminate the GI toxicity and/or GI irritation ofthe pharmaceuticals and/or nutraceuticals. In certain embodiments, thepharmaceutical and/or nutraceutical agents reduce, ameliorate, or treatinflammation. In other embodiments, the pharmaceutical and/ornutraceutical agents reduce, ameliorate, or treat platelet aggregation.In other embodiments, the pharmaceutical and/or nutraceutical agentsreduce, ameliorate, or treat pyretic activity. In other embodiments, thepharmaceutical and/or nutraceutical agents reduce, ameliorate, or treatulcerated regions of the tissue. Of course, the pharmaceutical and/ornutraceutical agents reduce, ameliorate, or treat combinations of thesesymptoms as well.

The disclosure is further described by reference to the followingexamples, which are provided for illustration only. The disclosed is notlimited to the examples, but rather includes all variations that areevident from the teachings provided herein. All publicly availabledocuments referenced herein, including but not limited to U.S. patents,are specifically incorporated by reference.

X. Definitions

The following terms have the meanings set forth below. In the presentdisclosure, singular and plural forms of words are used and should notbe seen to be expressly limited to the singular or plural form. Thus,reference to a carrier would also include reference to more the onecarrier and reference to carriers would include reference to a singlecarrier.

All ranges are inclusive meaning that they cover all subranges. Forexample, a range between about 10 and about 20 means any subrangebetween about 10 and about 20 such as about 10 to about 19, about 18,about 17, about 16, about 15, about 14, about 13, about 12, and about 11or about 11, about 12, about 13, about 14, about 15, about 16, about 17,about 18, about 19 to about 20 and any fraction range such as about 10.1to about 19.9, etc.

The term “mixture” means a blend of one or more ingredients, where theingredients may interact at the molecular level, e.g., a homogeneousmixture is a mixture, where the ingredients are uniformly andhomogeneously distributed, while an inhomogeneous mixture is a mixture,where the ingredients are not uniformly and homogeneously distributed.

The term “combination” means one or more ingredients that are combined,but not mixed.

The term “about” means 20% of an indicated value, within 15% of anindicated value, within 10% of an indicated value, within 5% of anindicated value, and/or within 1% of an indicated value. It should berecognized that the language of within 10% encompasses all valuesbetween 0% and 10% or ∀0 to ∀10% and is true for all of the otherranges.

The term “substantially” or “essentially” means that the attribute,condition or value is within 10% of an indicated value, within 7.5% ofan indicated value, within 5% of an indicated value, within 2.5% of anindicated value, within 1% of an indicated value, within 0.5% of anindicated value, within 0.1% of an indicated value, within 0.05% of anindicated value, within of an indicated value, within 0.005% of anindicated value, within 0.001% of an indicated value, within 0.0005% ofan indicated value, and/or within 0.0001% of an indicated value. Itshould be recognized that the language of within 10% encompasses allvalues between 0% and % or ∀0 to ∀10% and is true for all of the otherranges.

The term “essentially free” or “substantially free” means compositionsinclude less than or equal to about 5% (wt. % or vol. %) of a giveningredient, less than or equal to about 2.5% (wt. % or vol. %) of agiven ingredient, less than or equal to about 1% (wt. % or vol. %) of agiven ingredient, less than or equal to about 0.5% (wt. % or vol. %) ofa given ingredient, less than or equal to about 0.1% (wt. % or vol. %)of a given ingredient, less than or equal to about 0.05% (wt. % or vol.%) of a given ingredient, less than or equal to about 0.01% (wt. % orvol. %) of a given ingredient, less than or equal to about 0.005% (wt. %or vol. %) of a given ingredient, less than or equal to about 0.001%(wt. % or vol. %) of a given ingredient, less than or equal to about %(wt. % or vol. %) of a given ingredient, or less than or equal to about0.0001.% (wt. % or vol. %) of a given ingredient. Such ingredient mayinclude, without limitation, water, solvents, or any other ingredientthat is to be substantially excluded from the desired composition.Again, it should be recognized that the language of less than or equalto about 5% encompasses all values between about 0% and about 5% of thegiven ingredient.

The term “relatively high concentration” means that the pharmaceuticalor nutraceutical agents comprise greater than or equal to about 50 wt. %of the final composition, greater than or equal to about 55 wt. % of thefinal composition, greater than or equal to about 60 wt. % of the finalcomposition, greater than or equal to about 65 wt. % of the finalcomposition, greater than or equal to about 70 wt. % of the finalcomposition, greater than or equal to about 75 wt. % of the finalcomposition, greater than or equal to about 80 wt. % of the finalcomposition or greater than or equal to about 85 wt. % of the finalcomposition.

The term “major component” means a component present in a composition inan amount of at least about 33% (vol. % or wt. %) based on 100% of theformulations (vol. % or wt. %). In other embodiments, the term means atleast about 51% (vol. % or wt. %).

The term “minimally released” or “inefficiently released” means thatless than about 20% of a biologically active agent is released.

The term “maximally released” or “efficiently released” means thatgreater than about 50% of a biologically active agent is released orgreater than the amount released in low pH environments.

The term “association complex” or “associated complex” means anon-covalent association between two or more compounds, where thecompounds are held together by non-covalent chemical and/or physicalinteractions including hydrogen bonding, ionic bonding, dipolarinteractions, hyperpolarizible interactions, van der Waals interaction,electrostatic interaction, a polar bonding or interaction, or any otherchemical and/or physical attractive interaction.

The term “hydrophilic” means a compound having a strong affinity forwater; are soluble in water; tend to dissolve in, mix with, misciblewith water, or are wetted by water.

The term “hydrophobic” means a compound lacking affinity for water;insoluble in water; tends to repel water; or tends not to dissolve in,mix with, dissolve with, or are wetted by water.

The term “zwitterion” means a molecule that has a positively charged anda negatively charged functional group or moiety in the molecularstructure at biological pH levels.

The term “relatively hydrophobic barriers” means any external, internal,cellular or subcellular barrier that has hydrophobic properties, whichgenerally resists or reduces transport and/or partitioning ofhydrophilic reagents across the barrier. Such barriers include, withoutlimitation, a mucosal gel layer (e.g., gastric, duodenal, or colonicmucosal gel layers, vaginal mucosal gel layers, esophagus mucosal gellayers, nasal mucosal gel layers, lung mucosal gel layers, etc.), aplasma lemma (cellular membrane), the blood-brain barrier, placentalbarrier, testicular barrier, or any other barrier of a human, mammal oranimal, through which partitioning and/or transporting of hydrophobicmaterials more easily occurs than hydrophilic materials.

The term “residual water” means water remaining in components used tomake the compositions of this disclosure. Generally, the residual watercomprises a small impurity in the components of the compositions of thisdisclosure.

The term “minimal residual water” means that the compositions of thisdisclosure include less than about 5% (wt. % or vol. %) residual water,less than about 4% (wt. % or vol. %) residual water, less than about 3%(wt. % or vol. %) residual water, less than about 2% (wt. % or vol. %)residual water, less than about 1% (wt. % or vol. %) residual water,less than about 0.5% (wt. % or vol. %) residual water, less than about0.1% (wt. % or vol. %) residual water, less than about 0.05% (wt. % orvol. %) residual water, less than about 0.01% (wt. % or vol. %) residualwater, less than about 0.005% (wt. % or vol. %) residual water, or lessthan about 0.001% (wt. % or vol. %) residual water.

The term “low moisture” means that the compositions only includeresidual water found in the components used to make the compositions ofthis disclosure.

The term “targeted manner” or “targeted release” means that one or morebiologically active agents targeted for release into a desiredbiological environment.

The term “pH dependent manner” or “pH dependent release” means that oneor more biologically active agents for release into a desired biologicalpH environment. That is, the compositions release one or morebiologically active agents based on the pH of the biologicalenvironment. The carriers of the present disclosure operate to modify,alter, change, or augment chemical and/or physical characteristics ofthe one or more biologically active agents by providing animmiscible/different environment compared to an aqueous biofluid such asblood, gastric fluids, duodenal fluids, small intestinal fluids, largeintestinal fluids, vaginal fluids, rectal solids/fluids, or any otherbiofluid setting up a situation where the active agent is free topartition between the two immiscible environments. Additionally,properties of the carriers of this disclosure such as viscosity,lipophilicity, hydrophobicity, dispersibility, dispensability, softeningtemperature, melting temperature, etc. also act to modify, alter,change, or augment the rate of partitioning of the one or morebiologically active agents by sequestering the one or more biologicallyactive agents in the immiscible carrier until the carrier matrix isdispersed to small enough particles to facilitate mass transfer from theimmiscible carrier to the biofluid. For solid active agents sequesteredin a carrier matrix of this disclosure, an added reduction inpartitioning rate ensues because the solid must dissolve out of thematrix as the particle size of the matrix reduces in the biofluid due tomechanic actions of the tissue and/or organ and/or due to biochemicalprocesses occurring in the tissue and/or organ. Thus, the pH of thebiofluid changes the rate at which the immiscible carrier matrixdisperses in the biofluid and the mass transfer rates of the one or morebiologically active agents out of the carrier matrix. For weak acidactive agents and weak base active agents, the carrier may be designedto reduce release of the active agent until the pH of the biofluid is ator near (within about 1 pH unit or less) of the pKa or pKb of the activeagent. For a weak acid active agent, the carrier reduces release of theactive agent in low pH environments such as in gastric fluid, whichshowing increased release in pH environments at or near (within about 1pH unit or less) of the pKa of the weak acid active agent.

The term “one or more”, “at least one”, “one . . . or a plurality of . .. ” all mean a singular or more than one articles, components,ingredients, devices, etc.

The term “active agent” or “biologically active agent” or “activeingredient” or “biologically active ingredient”, which may beabbreviated as BAI or BAIs, means any pharmaceutical agent or activepharmaceutical ingredients (API) and/or any nutraceutical agent asdefined by the United State Food and Drug Administration (FDA).

The term “pharmaceutical agent” or “active pharmaceutical ingredients(APIs)” means any compound or composition that has been or will beapproved for human, mammal, and/or animal administration for treatingsome malady, disease, syndrome, dysfunction, etc.

The term “nutraceutical agent” means any compound or composition forhuman, mammal, and/or animal administration for nutritionalsupplementation or other uses.

The term “weak acid active agents or ingredients”, “weak acidbiologically active agents”, “weak base active agents or ingredients”,or “weak base biologically active agents or ingredients” or “weak acidor base active pharmaceutical ingredients (APIs)” are active agents thatare only partially ionized in aqueous solutions and the extent ofionization depends on the pH of the aqueous solution.

The term “anti-inflammatory drugs” mean any of a variety of drugs thatreduce or inhibit inflammation in tissue, organs, or the like.Anti-inflammatory drugs including non-steroidal, anti-inflammatory drugs(COX1 and/or COX2 inhibitors), drugs for treating irritable boweldisorder or disease (IBD) represents a family of ulcerative diseasesincluding Ulcerative Colitis and Crohn's Disease that affect the colonand distal small bowel, and other drugs that have anti-inflammatoryactivity in humans, mammals and/or animals. The present targeteddelivery systems may also find utility in treating conditions evidencinga pH imbalance in animal, mammals, and human GI, urinary, andreproductive tracts.

The term “NSAID” refers any of a variety of drugs generally classifiedas non-steroidal, anti-inflammatory drugs, including, withoutlimitation, ibuprofen, piroxicam, salicylate, aspirin, naproxen,indomethacin, diclofenac, COX2 inhibitors or any mixture thereof.

The term “oil” means any of numerous animal oils, vegetable oils,synthetic oils, animal fats, vegetable fats or synthetic fats that aregenerally slippery, combustible, viscous, liquid, or liquefiable at roomtemperature, soluble in various organic solvents such as ether, but notsoluble in or miscible with water.

The term “lipid” means any organic compounds including fats, oils,waxes, sterols, monoglycerides, di-glycerides, triglycerides, fatty acidesters, or the like that are insoluble in water but soluble in nonpolarorganic solvents and are oily to the touch.

The term “neutral lipid” (NL) as used in this application is not thetraditional meaning known in the art, but here means an uncharged,non-phosphoglyceride lipid, which includes triglycerides, fatty acidesters, other biocompatible oils, or any mixture thereof. In someembodiments, the term neutral lipid refers exclusively to triglycerides(TGs).

The term “phospholipid” (PL) means any naturally occurring or syntheticphospholipid.

The term “zwitterionic phospholipid” means any phospholipid bearing apositive and an negative charge at biological pHs including, withoutlimitation, phosphatidylcholine, phosphatidylserine,phosphalidylethanolamine, sphingomyelin and other ceramides, as well asvarious other zwitterionic phospholipids.

The term “biocompatible” means being compatible with living cells,tissues, organs, or systems, and posing no, minimal, or acceptable riskof injury, toxicity, or rejection by the immune system of a human,mammal, or animal.

The term “biocompatible agent” means any compound that is compatiblewith living cells, tissues, organs, or systems, and posing no risk ofinjury, toxicity, or rejection by the immune system of a human, mammal,or animal. There are a number of classes of biocompatible agentssuitable for use in the disclosure including hydrophobic biocompatibleagents, biocompatible oils, pH dependent biocompatible release agentssuch as biocompatible fatty acids or biocompatible fatty polyacids, andlecithin oils.

The term “biocompatible oil” means any oil that is compatible withliving cells, tissues, organs, or systems, and posing no risk of injury,toxicity, or rejection by the immune system of a human, mammal, oranimal. In certain embodiments, biocompatible oils are any oil that hasbeen approved for human consumption by the FDA or other governmentalagents or approved for of a human, mammal, or animal consumption, wherethe compound may be a solid or liquid at room temperature or biologicaltemperatures. In certain embodiments, the term means any oil that is afluid at biological temperatures. In other embodiments, the term meansany oil that is a fluid at room temperature. In the disclosure, whenoils are referenced, the term should be interpreted as biocompatibleoils.

The term “biocompatible fatty acid or biocompatible free fatty acid”means any fatty acid or free fatty acid (FFA) that is compatible withliving cells, tissues, organs, or systems of a human, mammal, or animal.In certain embodiments, biocompatible fatty acids are mono-carboxylicacids. In certain embodiments, the biocompatible fatty acids have atleast 8 carbon atoms. In other embodiments, the biocompatible fattyacids have at least 10 carbon atoms. In other embodiments, thebiocompatible fatty acids have at least 12 carbon atoms. In otherembodiments, the biocompatible fatty acids have at least 14 carbonatoms. In other embodiments, the biocompatible fatty acids have at least16 carbon atoms. In other embodiments, the biocompatible fatty acidshave at least 18 carbon atoms. In certain embodiments, the biocompatiblefatty acids may be unsaturated fatty acids. In certain embodiments, thebiocompatible fatty acids may be saturated fatty acids. In certainembodiments, the biocompatible fatty acids may be a mixture of saturatedand unsaturated fatty acids. The term “free fatty acid” is usedsometimes as a term to fully distinguish between a fatty acid (acarboxylic acid) and a fatty acid ester, a mono-glyceride, di-glyceride,and triglyceride. Again, the terms fatty acid or free fatty acid areused, the terms should be interpreted as biocompatible fatty acid orbiocompatible free fatty acid.

The term “biocompatible fatty acid ester” means any fatty acid esterthat is compatible with living cells, tissues, organs, or systems of ahuman, mammal, or animal. In certain embodiments, the biocompatiblecarboxylic acid esters are esters of mono-alcohols or polyols. Again,the term fatty acid ester is used, the term should be interpreted asbiocompatible fatty acid ester.

The term “biocompatible fatty acid salt” means any salt of abiocompatible fatty acid. In certain embodiments, the salts are salts ofmono-carboxylic fatty acids. Again, if the term fatty acid salt is used,the term should be interpreted as biocompatible fatty acid salt.

The term “biocompatible fatty poly acids” means any biocompatiblecompound having more than one carboxylic acid moiety per compound thatis compatible with living cells, tissues, organs, or systems of a human,mammal, or animal. In certain embodiments, the biocompatible poly acidshave at least 8 carbon atoms. In other embodiments, the biocompatiblepoly acids have at least 10 carbon atoms. In other embodiments, thebiocompatible poly acids have at least 12 carbon atoms. In otherembodiments, the biocompatible poly acids have at least 14 carbon atoms.In other embodiments, the biocompatible poly acids have at least 16carbon atoms. In other embodiments, the biocompatible fatty acids haveat least 18 carbon atoms. In certain embodiments, the biocompatiblefatty acids may be unsaturated fatty acids. In certain embodiments, thebiocompatible fatty acids may be unsaturated fatty acids. In certainembodiments, the biocompatible fatty acids may be saturated fatty acids.In certain embodiments, the biocompatible fatty acids may be a mixtureof saturated and unsaturated fatty acids. Again, the term fatty acidpoly acids should be interpreted as biocompatible fatty acid poly acids.

The term “lecithin” means a yellow-brownish fatty substances derivedfrom plant or animal and that is defined as complex mixture ofacetone-insoluble phosphatides, which consist chiefly ofphosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, andphosphatidylinositol, combined with various amounts of other substancessuch as triglycerides, fatty acids, and carbohydrates, as separated fromthe crude vegetable oil source. It contains not less than 50.0% ofacetone-insoluble matter. In certain embodiments, the lecithin maycomprise lipids esterified with unsaturated fatty acid side chains. Inother embodiments, the lecithin may be comprised of lipids withsaturated lipids. In other embodiments, the lecithin may be comprised oflipids with mixtures thereof.

The term “crude lecithin” means a lecithin containing having about 10-15wt. % phosphatidylcholine.

The term “semi crude or triple strength lecithin” means a lecithin wherethe phosphatidylcholine content has been increased to 35 wt. % to about50 wt %.

The term “lecithin oil” means a liquid lecithin where lecithin issolubilized in oil and/or a free fatty acid. In certain embodiments,this lecithin oil is a semi crude or triple strength lecithinsolubilized in a triglyceride and/or a free fatty acid.

The term “a purified phospholipid” means a naturally extracted orsynthetic phospholipid having a purity above at least 90 wt. % ofphospholipids, a single compound, or a class of closely relatedphospholipids such as phosphatidylcholine, phosphatidylethanol amine,dipalmitoylphosphatidylcholine (DPPC), or other similar phospholipids.Purified phospholipids are not lecithin, but may be derived fromlecithin through extraction and purification.

The term “targeted biocompatible release agent” or “targeted releaseagent” means an agent that controls the release of one or more activeagents in a targeted manner, i.e., release the active agents into aparticular tissue or organ depending on the tissue or organ'sphysiological environment.

The term “pH dependent biocompatible release agent” or “pH dependentrelease agent” means a targeted release agent that controls the releaseof one or more active agents in a pH dependent manner.

The term “carrier” means a composition that is a base for active agentssuch as pharmaceutical and/or nutraceutical agents.

The term “hydrophobic carrier” means a composition that is a base foractive agents such as pharmaceutical and/or nutraceutical agents, wherethe carrier including one or more or at least one hydrophobicbiocompatible agents and where the carrier is immiscible in water.

The term “oil-based carrier” means an oil-based composition that is abase for active agents such as pharmaceutical and/or nutraceuticalagents. The oil-based carriers comprise one or more biocompatible oilsand/or biocompatible hydrophobic agents and is a water immiscible.

The term “internal administration”, “internally administered” or“parenteral administration” means any non-enteral means ofadministration, but is generally interpreted as relating to injectingdirectly into the body, bypassing the skin and mucous membranes. Thecommon parenteral routes are intramuscular (IM), subcutaneous (SC) andintravenous (IV).

The term “enteral administration” means any non-parenteraladministration methods including oral administration (via the mouth),sublingual/buccal administration, rectal/vaginal administration,inhalation/inhaler administration, and/or topical administration.

EXPERIMENTS OF THE DISCLOSURE Example 1

This example illustrates the change in the form of a composition of thisdisclosure comprising a carrier including a fatty acid and atriglyceride as the composition is first placed in simulated gastricfluid, a low pH environment having a pH less than pH 3, second a base isadded to raise the pH to a high pH environment having a pH of 7, andthird an acid is added to lower the pH back to a pH less than pH 3.

1 gram of oleic acid and 9 grams of soybean oil is added to a beaker andstirred with a magnetic stirrer for 1 minute.

5 grams of the composition is added to a beaker equipped with a magneticstirrer and 50 mL of simulated gastric fluid is added with stirring. Itis expected that the composition does not distribute in the simulatedgastric fluid. To this material, a 1 N solution of sodium hydroxide isadded slowly to bring the pH up to about pH 7 with stirring. Raising thepH to pH 7 gives rise to a change in the carrier in a high pHenvironment. To this material, a 1 N solution of hydrochloride acid isadded slowly until the pH is lowered to the pH of the simulated gastricfluid. It is expected that the carrier will reorganize. Thus, a carriercomprising a sufficient amount of a fatty acid in a triglyceride iscapable of reorganization in a low pH environment, here simulatedgastric fluid. FIGS. 1 and 2 are designed to illustrate one possiblesequence of changes the carriers would undergo in transitioning from alow pH environment to a high pH environment and back to a low pHenvironment. The examples included hereinbelow include photographs ofactual changes in the compositions as they transition from a low pHenvironment to a high pH environment and back to a low pH environmentevidencing the nature of the initial form, the high pH form and thereconstituted form, which may or may not resemble the illustration ofFIGS. 1 and 2

Example 2

This example illustrates the change in the form of a composition of thisdisclosure comprising a carrier including a fatty acid and atriglyceride as the composition is first placed in simulated gastricfluid, a low pH environment having a pH less than pH 3, second a base isadded to raise the pH to a high pH environment having a pH of 7, andthird an acid is added to lower the pH back to a pH less than pH 3.

1 gram of oleic acid and 9 grams of soybean oil is added to a beaker andstirred with a magnetic stirrer for 1 minute.

5 grams of the composition is added to a beaker equipped with a magneticstirrer and 50 mL of simulated gastric fluid is added with stirring. Itis expected that the composition does not distribute in the simulatedgastric fluid. To this material, a 1 N solution of sodium hydroxide isadded slowly to bring the pH up to about pH 7 with stirring. Raising thepH to pH 7 gives rise to a change in the carrier in a high pHenvironment. To this material, a 1 N solution of hydrochloride acid isadded slowly until the pH is lowered to the pH of the simulated gastricfluid. It is expected that the carrier will reorganize. To this solutionis added 10 grams of powdered aspirin and the amount of aspirin in thesimulated gastric fluid and reorganized carrier are measured showingthat the aspirin partitions between the reorganized carrier and thesimulated gastric fluid. Thus, a carrier comprising a sufficient amountof a fatty acid in a triglyceride is capable of reorganization andabsorption of a BAI from the low pH fluid, here simulated gastric fluid.

Example 3

This example illustrates the change in the form of a composition of thisdisclosure comprising a carrier including a fatty acid and atriglyceride and aspirin in a 1:1 weight ratio as the composition isfirst placed in simulated gastric fluid, a low pH environment having apH less than pH 3, second a base is added to raise the pH to a high pHenvironment having a pH of 7, and third an acid is added to lower the pHback to a pH less than pH 3.

1 gram of oleic acid, 9 grams of soybean oil, and 10 grams of aspirinpowder is added to a beaker and stirred with a magnetic stirrer for 1minute.

5 grams of the composition is added to a beaker equipped with a magneticstirrer and 50 mL of simulated gastric fluid is added with stirring. Itis expected that the composition does not distribute in the simulatedgastric fluid. To this material, a 1 N solution of sodium hydroxide isadded slowly to bring the pH up to about pH 7 with stirring showing thechange in the carrier in a high pH environment and the release ofaspirin into the high pH environment. To this material, a 1 N solutionof hydrochloride acid is added slowly until the pH is lowered to the pHof the simulated gastric fluid. The carrier then reorganizes and theamount of aspirin in the simulated gastric fluid and reorganized carrierare measured showing that the aspirin partitions between the reorganizedcarrier and the simulated gastric fluid. Thus, a carrier comprising asufficient amount of a free fatty acid in a triglyceride is capable ofreorganization/reassembly in a low pH environment after BAI release in ahigh pH environment and the reorganized carrier is capable ofreabsorption of a BAI from the low pH fluid, here simulated gastricfluid.

Example 4

This example illustrates the construction of a set of experimentsdesigned to determine the influence of free fatty acid melting point,triglyceride melting point, nonionic surfactants and nonionic surfactantmelting point has on pH dependent carrier BAI release, pH dependentcarrier reorganization, reassembly, organization, or assembly andcarrier BAI absorption upon reorganization, reassembly, organization, orassembly after the carrier transitions from a low pH environment, to ahigh pH environment, and back to a low pH environment.

The experiments are set forth in the following tables, Table X and TableXI. Table X lists the reagents to be tested and their melting point whenavailable. Table XI tabulates the weight percentages of the reagentsused in the each test sample.

TABLE X Reagents to Be Tested Fatty Acid Nonionic Acid TriglycerideMethyl Esters Surfactant oleic acid soybean methyl sorbitan (OA) oil(SBO) linolenate (ML) monooleate (SMO) (mp = 16° C.) (mp = −16° C.) (mp= −52° C.) (liquid) lauric acid olive oil methyl oleate sorbitantrioleate (LA) (OO) (MO) (STO) (mp = 44° C.) (mp = −6° C.) (mp = −20°C.) (liquid) stearic acid palm oil methyl palmitate sorbitan (SA) (PO)(MP) tristearate(STS) (mp = 70° C.) (mp = 35° C.) (mp = 30.5° C.) (mp =53° C.)

TABLE XI Proposed Experiments Reagents Expressed in Percent Weight runOA LA SA SBO OO PO ML MO MP SMO STO STS 1 10 10 0 80 0 0 0 0 0 0 0 0 210 0 10 80 0 0 0 0 0 0 0 0 3 0 10 10 80 0 0 0 0 0 0 0 0 4 6.7 6.6 6.6 800 0 0 0 0 0 0 0 5 20 0 0 40 40 0 0 0 0 0 0 0 6 20 0 0 40 0 40 0 0 0 0 00 7 20 0 0 0 40 40 0 0 0 0 0 0 8 20 0 0 26.7 26.6 26.6 0 0 0 0 0 0 9 200 0 70 0 0 10 0 0 0 0 0

TABLE XII Proposed Experiments Reagents Expressed in Percent Weight runOA LA SA SBO OO PO ML MO MP SMO STO STS 10 20 0 0 70 0 0 0 10 0 0 0 0 1120 0 0 70 0 0 0 0 10 0 0 0 12 20 0 0 70 0 0 6.7 6.6 6.6 0 0 0 13 20 0 070 0 0 0 0 0 10 0 0 14 20 0 0 70 0 0 0 0 0 0 10 0 15 20 0 0 70 0 0 0 0 00 0 10 16 20 0 0 70 0 0 0 0 0 6.7 6.6 6.6

Example 5

This example illustrates a designed set of experiments to illustrate theinfluence of polyacids on the assembly of carrier that transition from alow pH environment to a high pH environment and back.

The experiments are set forth in the following tables, Table XIII andTable XIV. Table XIII lists the reagents to be tested and their meltingpoint when available. Table XIV tabulates the weight percentages of thereagents used in each test run.

TABLE XIII Reagents to Be Tested Acid Triglyceride Poly Acids NonionicSurfactant oleic acid soybean Glutaric acid (GA) sorbitan trioleate (OA)oil (SBO) EUDRAGIT ® L (EL)* (STO) EUDRAGIT ® E (EE)** HPMC-P*EUDRAGIT ® L: poly(methacrylic acid-co-methyl methacrylate)**EUDRAGIT ® E: copolymer of dimethylaminoethyl methacrylate, butylmethacrylate, and methyl methacylate

TABLE XIV Proposed Experimental Reagents Expressed in Weight Percent runOA SBO GA EL EE HPMC-P STO 1 20 80 0 0 0 0 0 2 20 70 10 0 0 0 0 3 20 700 10 0 0 0 4 20 70 0 0 10 0 0 5 20 70 0 0 0 10 0 6 20 70 2.5 2.5 2.5 2.50 7 20 70 5 0 0 0 5

TABLE XV run OA SBO GA EL EE HPMC-P STO 8 20 70 0 5 0 0 5 9 20 70 0 0 50 5 10 20 70 0 0 0 5 5 11 20 60 2.5 2.5 2.5 2.5 5

Example 6

This example illustrates whether the compositions of EXAMPLE 4 oncereorganized, reassembled, organized, or assembled after the carriertransitions from a low pH environment, to a high pH environment, andback to a low pH environment, absorb aspirin via partitioning away fromthe simulated gastric fluid.

Example 7

This example illustrates whether the compositions of EXAMPLE 5 oncereorganized, reassembled, organized, or assembled after the carriertransitions from a low pH environment, to a high pH environment, andback to a low pH environment, absorb aspirin via partitioning away fromthe simulated gastric fluid.

Example 8

This example illustrates the preparation of a set of examples designedto determine the relative concentrations of carrier ingredient tosimultaneously optimize pH dependent BAI release and carrier reassemblyor reformulation due to duodenal reflux. Each ingredient is designed toserve competing strategies including sacrificial agents, stabilizationagents, and improved hydrophobic characteristic upon reassembly orreformulation in a low pH environment.

TABLE XVI Ingredient wt. % wt. % wt. % wt. % wt. % wt. % wt. % wt. % wt.% oleic acid 20 30 40 40 20 40 20 35 17.5 stearic acid 5 0 0 0 0 0 0 0 0palmitic acid 5 10 0 0 20 0 20 0 17.5 a polymer including at least 5 510 10 10 0 0 0 0 20 % acrylic acid remainder ethylene soybean oil 40 3540 20 40 60 30 55 27.5 coconut oil 10 10 0 20 0 0 30 0 27.5 phospholipid5 0 0 0 0 0 0 0 0 lower MW nonionic 5 5 5 5 5 0 0 5 5 surfactant higherMW nonionic 5 5 5 5 5 0 0 5 5 surfactant Totals 100 100 100 100 100 100100 100 100

Experiments Designed to Simulate Duodenal Reflux and to TestReconstitution and Api Reabsorption

The following examples describe a procedure to simulate duodenal reflux.Duodenal reflux is a process by which material from the stomach entersthe duodenum through the pyloric sphincter and a portion of the materialflows back into the stomach when the pyloric sphincter opens and closes.The simulated duodenal reflux procedure involves subjecting a sample ofa suspension of an API in an oil based carrier to a pH cycle comprisingadding the sample to an aqueous 0.1 N HCl solution having a pH of aboutpH 1 (simulated gastric fluid) with stirring, adding NaOH to the mixturewith stirring to raise the pH to about pH 7 (simulated duodenal fluid),and finally adding concentrated HCl to the mixture with stirring tolower the pH to about pH 1 (simulated gastric fluid). Photographs aretaken during all stages of the procedure to document changes in thesample during pH cycling. Analytical samples are taken from the oilphase and the aqueous phase of each of the solutions to determine APIconcentrations in oil phase and the aqueous phase of each of thesolutions. The analytical samples were subjected to UV analysis tomeasure API concentrations in each of the phases of the solutions. UVanalysis is suitable for APIs that include UV detectable groups such ascarbonyl groups, carboxylic acid group, aromatic rings, or other groupsusceptible to UV analysis, especially APIs that include aromatic rings.Aspirin, ibuprofen and omeprazole are APIs that include aromatic ringsthat make UV analysis straight forward. Proteins are also APIs that areamendable to UV analysis as most proteins include at least one of thearomatic ring containing amino acids phenylalanine, tryptophan, andtyrosine.

Example 9. Control Composition Preparation and pH Cycle Testing

This example illustrates the preparation of a sample of a controlcomposition subject to the duodenal reflux procedure outlined above.

The control composition included the following ingredients:

TABLE XVII Quantity per Unit Quantity Ingredient (mg) (g) Citric AcidAnhydrous Powder USP/EP 7.48 7.48 Lecithin 15.78 15.82 Oleic Acid NF/EP19.27 19.27 Soybean Oil-IV 41.62 41.65 Total 84.15 84.22

Control Composition Preparation Procedure

The control composition was prepared as follows:

-   -   1. Screen citric acid through a 40 mesh hand screen;    -   2. Add oleic acid, soybean oil, and lecithin into a beaker and        heat the mixture while stirring with a stir bar on a hot plate        until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity; and    -   4. Continue stirring the mixture during testing to maintain        uniformity.

Control Composition pH Cycle Test Procedure

The control composition pH cycle test was performed as follows:

-   -   1. Place 10 grams of the control composition in a 150 mL beaker        containing 100 mL of a 0.1 N HCl solution having a pH of about        1, simulated gastric fluid;    -   2. Observe and photograph the control composition in the pH 1        solution;    -   3. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7,        simulated duodenal fluid;    -   4. Observe and photograph the control composition in the pH 7        solution;    -   5. Add concentrated HCl to the beaker with stirring while        monitoring the pH with the pH meter until the pH is about 1,        back to the simulated gastric fluid; and    -   6. Observe and photograph the control composition in the pH 1        solution.

Example 10. Aspirin-Containing Composition Preparation and pH CycleTesting

This example illustrates the preparation of a sample of anaspirin-containing composition subject to the duodenal reflux procedureoutlined above.

The aspirin-containing composition included the following ingredients:

TABLE XVIII Quantity per Unit Quantity Ingredient (mg) (g) Aspirin (ASA)81 81 Citric Acid Anhydrous Powder USP/EP 7.48 7.48 Lecithin 15.78 15.82Oleic Acid NF/EP 19.27 19.27 Soybean Oil-IV 41.62 41.62 Total 165.15165.19

Aspirin-Containing Composition Preparation Procedure

-   -   The aspirin-containing composition was prepared as follows: 1.        Screen citric acid and aspirin (ASA) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, and lecithin into a 150 mL        beaker and heat the mixture while stirring with a stir bar on a        hot plate to until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add aspirin to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Aspirin-Containing Composition pH Cycle Test Procedure

The aspirin-containing composition pH cycle test was performed asfollows:

-   -   1. Place 10 g of the aspirin-containing composition in a 150 mL        beaker containing 100 mL of a 0.1 N HCl solution having a pH of        about 1, simulated gastric fluid;    -   2. Observe and photograph the aspirin-containing composition in        the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7,        simulated duodenal fluid;    -   5. Observe and photograph the aspirin-containing composition in        the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with the pH meter until the pH is about 1;    -   8. Observe and photograph the aspirin-containing composition in        the pH 1 solution, back to simulated gastric fluid; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Control and Aspirin-Containing Samples Photographs ofMixing, pH Monitoring, and Temperature Monitoring

Referring now to FIG. 3 , photographs are shown the illustrate themixing and monitoring procedures described above. FIG. 3 includes aphotograph showing a pH meter and two photographs showing how thesamples were mixed and how sample temperature and pH were monitored.Heating was controlled using a hot plate and monitored by a thermometer,and pH monitoring was monitored by the pH meter.

Photographs of Control Composition During pH Cycle

Referring now to FIG. 4 , photographs show the control composition in aninitial pH 1 solution (left photograph), in a pH 7 solution afterconcentrated NaOH addition to the initial pH 1 solution (middlephotograph), and in a final pH 1 solution after concentrated HCladdition to the pH 7 aqueous solution (right photograph). The controlcomposition is clearly immiscible in the initial pH 1 solution. When thepH is raised to pH 7, a change in the look of the control compositionmay be seen: compare the far left photograph to the middle photograph.At pH 7, the control composition appears to break apart in several oilphases, a lower density oil phase and a higher density oil phase and theaqueous phase appears slightly cloudy. The oil and aqueous phases stillappear to be substantially immiscible in the pH 7 solution. When the pHof the pH 7 solution is lowered back to pH 1, the aqueous phaseclarifies, while the oil phase now appears similar to its starting form.

Photographs of Aspirin-Containing Composition During pH Cycle

Referring now to FIG. 5 , photographs show the aspirin-containingcomposition in an initial pH 1 solution, in a pH 7 solution afterconcentrated NaOH addition to the initial pH 1 solution, and in a finalpH 1 solution after concentrated HCl addition to the pH 7 solution. Notethat the aspirin-containing composition is denser than the initial pH 1aqueous solution, a difference from the control composition. When the pHof the initial pH 1 solution is raised to pH 7, a change in the look ofthe aspirin-containing composition may be seen: compare the far leftphotograph to the middle photograph. At pH 7, the aspirin-containingcomposition is still immiscible in the aqueous phase, but now is lessdense than the pH 7 aqueous phase and the aqueous phase of the pH 7solution is slightly cloudy. When the pH of the pH 7 solution is loweredback to pH 1, the aqueous phase still slightly cloudy, while the oilphase appears lighter in color than at the start, but after sitting fora while, the oil phase gains back is normal color, but remains lighterthan the final pH 1 aqueous phase.

Clearly, the control composition and the aspirin-containing compositionmaintain their essential immiscible in the aqueous phases during a pHcycle.

Referring now to FIG. 6 , photographs show the aspirin-containingcomposition after concentrated NaOH addition to raise the pH back to pH7. The aqueous phase is still slightly cloudy, while the oil phaseremains less dense than the aqueous solutions in both pH 7 solutions.

Referring now to FIG. 7 , photographs show a comparison of varioussamples including from left to right: the control composition (Control)in the initial pH 1 solution, the aspirin-containing composition (ASA)in the pH 7 solution, the aspirin-containing composition (ASA) in theinitial pH 1 aqueous solution, the aspirin-containing composition (ASA)in the first pH 7 solution, the aspirin-containing composition (ASA) inthe final pH 1 solution, and the aspirin-containing composition (ASA) inthe second pH 7 solution. In all cases, the pH 7 solutions are slightlycloudy, while the pH 1 aqueous solution are clear.

Uv Analysis of Aspirin-Containing Samples Aspirin (ASA) UV Analysis

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis. Aspirin (ASA) is the onlyingredient in the sample that includes an aromatic ring and has adistinct UV absorption; as aspirin is known to hydrolysis in water tosalicylic acid (SA), SA was also analyzed. UV spectral analysis was usedto determine the concentration of ASA and SA in the UV detectionsamples. The following table includes ASA/SA concentrations asdetermined by UV spectral analysis:

TABLE XIX UV Aspirin (ASA) Phase Concentration Data in mg/mL pH ofSolutions Samples 1 (start) 7 1 (end) Oil Phase: ASA analysis 0.83920.3182 0.6500 Aqueous Phase: ASA analysis 0.2092 0.3653 0.2751 OilPhase: SA analysis 0.1013 0.0417 0.0780 Aqueous Phase: SA analysis0.0042 0.1382 0.0231 Oil Phase: ASA + SA analysis 0.9405 0.3599 0.7280Aqueous Phase: ASA + SA analysis 0.2135 0.5034 0.2982 Total ASA + SA inboth phases 1.1539 0.8633 1.0262

Referring now to FIG. 8 , a plot of the UV aspirin (ASA) and salicylicacid (SA) concentration values for the various phases of theaspirin-containing composition during the pH cycle experiment is shown.Initially, the ASA (aspirin) and SA (salicylic acid) are primarily inthe oil phase with 0.9405 mg/mL (81.5%) in the oil phase compared to0.2135 mg/mL (18.5%) in the aqueous phase. When the pH is raised to pH7, the ASA (aspirin) and SA (salicylic acid) are present in the aqueousphase to a greater degree than in the oil phase with 0.5034 mg/mL(58.3%) in the aqueous phase compared to 0.3599 mg/mL (41.7%) in the oilphase. When the pH is lowered back to pH 1, a large amount of the ASA(aspirin) and SA (salicylic acid) from the aqueous phase is reabsorbedinto the oil phase with 0.7280 mg/mL (70.9%) in the oil phase comparedto 0.2982 mg/mL (29.1%) in the aqueous phase.

The inventors believe that this reconstitution and reabsorption is acontributing factor to the superior GI safety of the NSAID formulationsof this disclosure. It appears that a sufficient amount of a freecarboxylic acid in the carrier is responsible not only for the carrier'sextreme hydrophobicity as evidenced that the carrier is immiscible in pH1 aqueous solutions, where the API, here aspirin, is primarily presentin the oil phase. The data also show that in the pH 7 solution, the API,aspirin here, is released into the aqueous phase, where a larger amountof aspirin is now present in the pH 7 aqueous phase. The data alsoclearly show that the API, aspirin here, is reabsorbed into the carrierwhen the pH is lowered back to pH of about 1 reducing the amount of APIin the aqueous phase. These findings are consistent with the improved GIsafety of the compositions of this disclosure including an effectiveamount of free carboxylic acids, as the reconstitution and reabsorptiondecreases aspirin concentration in the stomach during duodenal reflux.

Example 11. Ibuprofen-Containing Composition Preparation and pH CycleTesting

This example illustrates the preparation of a sample of anibuprofen-containing composition subject to the duodenal refluxprocedure outlined above.

The ibuprofen-containing composition included the following ingredients:

TABLE XX Quantity per Unit Quantity Ingredient (mg) (g) Ibuprofen (IBU)81 81 Citric Acid Anhydrous 7.48 7.48 Powder USP/EP Lecithin 15.78 16.04Oleic Acid NF/EP 19.27 19.29 Soybean Oil-IV 41.62 41.62 Total 165.15165.43

Ibuprofen-Containing Composition Preparation Procedure

The ibuprofen-containing composition was prepared as follows:

-   -   1. Screen citric acid and ibuprofen (IBU) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, and lecithin into a 150 mL        beaker and heat the mixture while stirring with a stir bar on a        hot plate to until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add ibuprofen to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Ibuprofen-Containing Composition pH Cycle Test Procedure

The ibuprofen-containing composition pH cycling was performed asfollows:

-   -   1. Place 10 grams ibuprofen-containing composition in a 150 mL        beaker including 100 mL of a 0.1 N HCl solution having a pH of        about 1;    -   2. Observe and photograph the ibuprofen-containing composition        in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the ibuprofen-containing composition        in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the ibuprofen-containing composition        in the pH 1 solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Ibuprofen-Containing Composition

Referring now to FIG. 9 , photographs show the ibuprofen-containingsample in an initial pH 1 solution (left photograph), in the pH 7solution after concentration NaOH addition to the initial pH 1 solution,(middle photograph), and in the final pH 1 solution after concentrationHCl addition to the pH 7 solution (right photograph). Theibuprofen-containing composition is also clearly immiscible in theinitial pH 1 solution. Note that a majority of the ibuprofen-containingcomposition is slightly less dense than the initial pH 1 solution. Whenthe pH is raised to pH 7, a significant change in the look of theibuprofen-containing composition may be seen: compare the leftphotograph to the middle photograph. At pH 7, the ibuprofen-containingcomposition appears to form a mixture of the oils phase dispersed in theaqueous phase similar to an emulsion. When the pH is lowered back to pH1, the aqueous phase of the final pH 1 solution clarifies, while the oilphase appears to reconstitute into two phases, one less dense than theaqueous phase and one more dense than the aqueous phase.

Referring now to FIG. 10 , photographs show the pH cycleibuprofen-containing samples after 1 day and after 4 days. The day 4photograph clearly show that the oil has reconstituted into two phases,one less dense than the aqueous phase and one more dense than theaqueous phase and the aqueous phase is clarified. Again, the photographsclearly show that the oil have is immiscible in the pH 1 solutions.

UV Analysis of Ibuprofen-Containing Composition Ibuprofen (IBU) UVAnalysis

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as aspirin (ASA) is the onlygroup that absorbs UV light due to the presence of an aromatic ring. Thefollowing table includes the ASA UV results:

TABLE XXI UV Ibuprofen (IBU) Phase Concentration Data in mg/mL andPercentages IBU in Less IBU in IBU in IBU Total in Percent Dense AqueousDenser Both IBU in Solution Oil Phase Phase Oil Phase Phases Oil PhasepH 1 1.5918 0.0040 1.5923 99.97% pH 7 0.6373 0.5752 1.2125 52.56% pH 11.0010 0.2280 0.0255 1.2545 79.79%

Referring now to FIG. 11 , the UV ibuprofen concentration values for theibuprofen-containing composition in the pH 1 solutions and the pH 7solution during the pH cycle experiment. Initially, essentially all ofthe ibuprofen is in the oil phase: 1.5918 mg/mL (99.97%) of ibuprofen inthe oil phase compared to 0.0040 mg/mL (0.03%) in the aqueous phase.When the pH is raised to pH 7, the ibuprofen partitions almost equallyin the aqueous phase and the oil phase: 0.6373 mg/mL (52.56%) in the oilphase compared to 0.5752 mg/mL (47.44%) in the aqueous phase. When thepH is lowered back to pH 1, a large amount of the ibuprofen isreabsorbed into the oil phase: 1.0010 (79.79%) in the oil phase comparedto 0.2280 (20.21%) in the aqueous phase.

Again, the inventors believe that this reconstitution and reabsorptionis a contributing factor to the superior GI safety of carriers of thisdisclosure. It appears that a sufficient amount of a free carboxylicacid in the carrier is responsible not only for the carrier's extremehydrophobicity as carrier is essentially immiscible in the initial pH 1aqueous solution, where the API, here ibuprofen, is primarily present inthe oil phase. The data also show that in the pH 7 solution, the API,ibuprofen here, is released into the aqueous phase, where almost equalamounts of ibuprofen are found in the two phases. The data also clearlyshow that the API, ibuprofen here, is reabsorbed into the carrier whenthe pH is lowered back to pH of about 1 reducing the amount of API inthe aqueous phase. These findings are consistent with the improved GIsafety of the compositions of this disclosure including an effectiveamount of free carboxylic acids.

Example 12. Omeprazole-Containing Composition Preparation and pH CycleTesting

This example illustrates the preparation of a sample of anomeprazole-containing composition subject to the duodenal refluxprocedure outlined above.

The omeprazole-containing composition included the followingingredients:

TABLE XXII Quantity per Unit Quantity Ingredient (mg) (g) Omeprazole(OZ) 81 81 Citric Acid Anhydrous Powder USP/EP 7.48 7.48 Lecithin 15.7816.04 Oleic Acid NF/EP 19.27 19.29 Soybean Oil-IV 41.62 41.62 Total165.15 165.43

Omeprazole-Containing Composition Preparation Procedure

The omeprazole-containing composition was prepared as follows:

-   -   1. Screen citric acid and omeprazole (OZ) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, and lecithin into a 150 mL        beaker and heat the mixture while stirring with a stir bar on a        hot plate to until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add omeprazole to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Omeprazole-Containing Composition pH Cycle Test Procedure

The omeprazole-containing composition pH cycling was performed asfollows:

-   -   1. Place 10 grams omeprazole-containing composition in a 150 mL        beaker including 100 mL of a 0.1 N HCl solution having a pH of        about 1;    -   2. Observe and photograph the omeprazole-containing composition        in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the omeprazole-containing composition        in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the omeprazole-containing composition        in the pH 1 solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of the Omeprazole-Containing Composition

Referring now to FIG. 12 , photographs of the preparation of theomeprazole-containing composition. Photograph (a) shows omeprazole intothe carrier to form the omeprazole-containing composition. Initially,the omeprazole-containing composition is a brown and upon citric acidaddition, the omeprazole-containing composition begins to turn purpleand after a little stirring turned deep purple. The inventors believethat the color change in due to the protonation of omeprazole. Theinventors do not know why the color change happened only after citricacid addition as the matrix includes a large amount of oleic acid.

Referring now to FIG. 13 , photographs of the omeprazole-containingcomposition after initial addition to the pH 1 solution, after pHadjustment of the pH 1 solution, and one minute after pH adjustment.Upon initial addition of the omeprazole-containing composition to the pH1 solution, the omeprazole-containing composition sinks to the bottomand the aqueous phase turns brown. The initial pH of the solution wasnot at pH 1, but was at a pH about 2. The inventors believe that therise in pH was due to the protonation of omeprazole. After adjusting thepH to 1, the solution turned darker, but after setting for about oneminute, the omeprazole-containing composition is still at the bottom,and the aqueous phase is still brown.

Referring now to FIG. 14 , photographs of the omeprazole-containingcomposition show the omeprazole-containing composition as the pH of thepH 1 solution is raised to pH 7. The solution turned purple with the oilphase distributed in the solution.

Referring now to FIG. 15 , photographs of the control composition priorto addition to a solution (left photograph), the omeprazole-containingcomposition prior to addition to a solution (next photograph), theomeprazole-containing composition after addition to the pH 1 solution(next photograph), the omeprazole-containing composition after raisingthe pH to pH 7 (next photograph), and the omeprazole-containingcomposition after lowering the pH to pH 1 (next photograph): a pH cycle.The control composition is a light yellow oil. The omeprazole-containingcomposition is a deep purple. The omeprazole-containing compositionafter addition to the pH 1 solution settled to the bottom and theaqueous solution is a brown color. The omeprazole-containing compositionafter raising the pH to pH 7 is distributed throughout the aqueoussolution and the mixture is deep purple in color. Theomeprazole-containing composition after lowering the pH of the solutionback to pH 1 settled to the bottom and the aqueous solution is a darkbrown to purple color.

Uv Analysis of the Omeprazole-Containing Composition Omeprazole (OZ) UVAnalysis of the Omeprazole-Containing Composition

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as omeprazole (OZ) is the onlygroup that absorbs UV light due to the presence of an aromatic ring. Thefollowing table includes the OZ UV results:

TABLE XXIII UV Omeprazole (OZ) Phase Concentration Data in mg/mL andPercentages OZ in Oil OZ Aqueous OZ in Oil OZ in Aqueous Phase PhasePhase Phase Solution (mg/mL) (mg/mL) (%) (%) pH 1 3.2 1.78 64.40 35.60pH 1-7 4.50 0.50 90.00 10.00 pH 1-7-1 1.97 3.03 39.40 61.60

Referring now to FIG. 16 , a plot of UV omeprazole (OZ) concentrationvalues of the omeprazole-containing composition in the oil and aqueousphases during a pH cycle. Initially, 3.2 mg/mL (64.40%) of omeprazole isin the oil phase and 1.78 mg/mL (35.60%) of omeprazole in the aqueousphase. When the pH is raised to pH 7, the omeprazole partitions from theaqueous phase and the oil phase resulting in 4.50 mg/mL (90.00%) in theoil phase compared to 0.50 mg/mL (10.00%) in the aqueous phase. When thepH is lowered back to pH 1, the concentration in the aqueous phase isnow larger the composition of omeprazole in the oil phase: 1.97 mg/mL(39.40%) in the oil phase compared to 3.03 (61.60%) in the aqueousphase.

The behavior of the omeprazole during preparation and during pH cycletesting is fundamentally different from the behavior of aspirin andibuprofen. The inventors believe that the difference in behavior is dueto the fact that omeprazole has groups that may be protonated ordeprotonated as shown below:

The inventors believe that the cation form of omeprazole may beresponsible for the deep purple color in the oil matrix and may bereason for the brown color of the pH 1 solution and the color of the pH7 solution. Interestingly, omeprazole partitions into the oil phase oncethe pH is raised to pH 7 and the omeprazole is in its neutral form.While the pH behavior of omeprazole is not the same as the pH behaviorof aspirin and ibuprofen, the behavior of omeprazole still shows pHdependent release. The more significant observation is the fact thatomeprazole is almost exclusively in the oil phase at pH 7. Based on thechemistry of omeprazole shown above, this behavior is not inconsistentwith the UV determined concentrations of omeprazole during pH cycling.While the direction of the pH dependent phase concentration is differentfrom aspirin and ibuprofen, the inventors believe that the absorption ofomeprazole into the oil phase at pH 7 may increase the absorption ofomeprazole in the duodenum.

Referring now to FIG. 17 , a plot comparing UV aspirin, ibuprofen, andomeprazole concentration during a pH cycle. The plot clearly shows thedifference in pH cycle behavior during pH cycling. Thus, the inventorsbelieve that the pH behavior of pharmaceuticals in the oil carriers ofthis disclosure may be determined based on the structure of thepharmaceutical. If the structure includes a group that protonates at pH1 and deprotonates at pH 7, the pH dependent behavior should mimicomeprazole. If the structure does not include a protonatable group at pH1, then the pH dependent behavior should mimic aspirin and ibuprofen. Ifthe structure includes a group that deprotonates at pH 7, then the pHdependent behavior should show much greater release at pH 7 than aspirinor ibuprofen. Thus, pharmaceutical compounds may be easily separatedinto three classes: class 1 pharmaceutical compounds are compounds thatinclude a group that protonates at pH 1 and deprotonates at pH 7, class2 pharmaceutical compounds are compounds that do not include a groupthat protonates at pH 1 and deprotonates at pH 7, and class 3pharmaceutical compounds are compounds that a group that deprotonates atpH 7. However, the inventors believe that this classification scheme mayonly be amenable to simple pharmaceutical compounds. More complexpharmaceutical compounds such as proteins, polypeptide, DNA, RNA,enzymes, or the like may have different pH dependent behavior, which maybe elucidated based on the pH dependent behavior of soy isolatedescribed herein.

Example 13. High Oleic Acid-Ibuprofen-Containing Composition Preparationand pH Cycle Testing

This example illustrates the preparation of a sample of aibuprofen-containing composition, where the oil matrix includes 50%oleic acid and 50% soybean oil and the pH cycle behavior during theduodenal reflux procedure outlined above.

The high oleic acid-ibuprofen-containing composition included thefollowing ingredients:

TABLE XXIV Quantity per Unit Quantity Ingredient (mg) (g) ibuprofen20.25 20.25 citric acid anhydrous powder USP/EP 1.87 1.87 lecithin 3.953.95 oleic acid NF/EP 7.61 7.61 soybean oil-IV 7.61 7.61 Total 41.2941.29

High Oleic Acid-Ibuprofen-Containing Composition Preparation

The high oleic acid-ibuprofen-containing composition was prepared asfollows:

-   -   1. Screen citric acid and ibuprofen (IBU) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, and lecithin into a 150 mL        beaker and heat the mixture while stirring with a stir bar on a        hot plate to until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add ibuprofen to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

High Oleic Acid-Ibuprofen-Containing Composition pH Cycle Test

The high oleic acid-ibuprofen-containing composition pH cycling wasperformed as follows:

-   -   1. Place 10 grams the high oleic acid-ibuprofen-containing        composition in a 150 mL beaker including 100 mL of a 0.1 N HCl        solution having a pH of about 1;    -   2. Observe and photograph the high oleic        acid-ibuprofen-containing composition in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the high oleic        acid-ibuprofen-containing composition in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the high oleic        acid-ibuprofen-containing composition in the pH 1 solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of High Oleic Acid-Ibuprofen-Containing Composition

Referring now to FIG. 18 , photographs of the high oleicacid-ibuprofen-containing composition in the pH 1 solution, the higholeic acid-ibuprofen-containing composition in the solution afterconcentrated NaOH addition to raise the pH to pH 7, and the high oleicacid-ibuprofen-containing composition in the solution after concentratedHCl addition to lower the pH back to pH 1. The photographs show that thehigh oleic acid-ibuprofen-containing composition is immiscible in the pH1 solutions and forms an emulsion in the pH 7 solution. The high oleicacid-ibuprofen-containing composition behaves a little differently fromthe low oleic acid-ibuprofen composition in the pH 7 solution as theemulsion seems to be a little better formed. In fact, FIG. 19 shows thatthe high oleic acid-ibuprofen-containing composition forms an emulsionvery similar to the emulsion produced when the control composition inthe pH 7 solution after concentrated NaOH addition to raise the pH ofthe pH 1 solution to pH 7.

UV Analysis of High Oleic Acid-Ibuprofen-Containing CompositionIbuprofen (IBU) UV Analysis of the High Oleic Acid-Ibuprofen-ContainingComposition

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as ibuprofen (IBU) is the onlycompound that having an aromatic ring. The following table includes theIBU UV concentration results:

TABLE XXV UV Ibuprofen (IBU) Phase Concentration Data in mg/mL andPercentages IBU in Oil IBU Aqueous IBU in IBU in Phase Phase Both PhasesOil Phase Solution (mg/mL) (mg/mL) (mg/mL) (%) pH 1 0.5840 0.0078 0.591898.69% pH 1-7 0.3515 0.2092 0.5608 62.68% pH 1-7-1 0.3736 0.0077 0.381297.99%

Referring now to FIG. 20 , the UV ibuprofen concentration values for theibuprofen-containing sample in the pH 1 solutions and the pH 7 solutionduring the pH cycle. Initially, essentially all of the ibuprofen is inthe oil phase: 0.5840 mg/mL (98.69%) of ibuprofen in the oil phasecompared to 0.0078 mg/mL (1.31%) in the aqueous phase. When the pH israised to pH 7, the ibuprofen partitions between the phases with 0.3515mg/mL (62.68%) in the oil phase compared to 0.2092 mg/mL (37.32%) in theaqueous phase. When the pH is lowered back to pH 1, a large amount ofthe ibuprofen is reabsorbed into the oil phase: 0.3786 (97.99%) in theoil phase compared to 0.0077 (2.01%) in the aqueous phase. The highamount of oleic acid in the composition resulted in a largerreabsorption compared to the lower amount of oleic acid in thecomposition.

Again, the inventors believe that this reconstitution and reabsorptionis a contributing factor to the superior GI safety of carriers of thisdisclosure. It appears that a sufficient amount of a free carboxylicacid in the carrier is responsible not only for the carrier's extremehydrophobicity as carrier is essentially immiscible in the initial pH 1aqueous solution, where the API, here ibuprofen, is primarily present inthe oil phase. The data also show that in the pH 7 solution, the API,ibuprofen here, is released into the aqueous phase, where almost equalamounts of ibuprofen are found in the two phases. The data also clearlyshow that the API, ibuprofen here, is reabsorbed into the carrier whenthe pH is lowered back to pH of about 1 reducing the amount of API inthe aqueous phase. These findings are consistent with the improved GIsafety of the compositions of this disclosure including an effectiveamount of free carboxylic acids.

Example 14. Nonionic Surfactant-Ibuprofen-Containing CompositionPreparation and pH Cycle Testing

This example illustrates the preparation of a sample of a nonionicsurfactant-ibuprofen-containing composition subject to the duodenalreflux procedure outlined above.

The nonionic surfactant-ibuprofen-containing composition included thefollowing ingredients:

TABLE XXVI Quantity per Unit Quantity Ingredient (mg) (g) Ibuprofen(IBU) 81 81 Citric Acid Anhydrous Powder USP/EP 7.48 7.48 Lecithin 15.7816.04 GATTEFOSSÉ LAUROGLYCOL ™ 90 0.52 0.52 Nonionic Surfactant OleicAcid NF/EP 19.27 19.29 Soybean Oil-IV 41.62 41.62 Total 165.67 165.95

Nonionic Surfactant-Ibuprofen-Containing Composition PreparationProcedure

The nonionic surfactant-ibuprofen-containing composition was prepared asfollows:

-   -   1. Screen citric acid and ibuprofen (IBU) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, nonionic surfactant        (GATTEFOSS{tilde over (E)} LAUROGLYCOL™ 90), and lecithin into a        150 mL beaker and heat the mixture while stirring with a stir        bar on a hot plate to until the mixture achieves visual        uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add ibuprofen to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Nonionic Surfactant-Ibuprofen-Containing Composition pH Cycle TestProcedure

The nonionic surfactant-ibuprofen-containing composition pH cycling wasperformed as follows:

-   -   1. Place 10 grams nonionic surfactant-ibuprofen-containing        composition in a 150 mL beaker including 100 mL of a 0.1 N HCl        solution having a pH of about 1;    -   2. Observe and photograph the nonionic        surfactant-ibuprofen-containing composition in the pH 1        solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the nonionic        surfactant-ibuprofen-containing composition in the pH 7        solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the nonionic        surfactant-ibuprofen-containing composition in the pH 1        solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Nonionic Surfactant-Ibuprofen-Containing Composition

Referring now to FIG. 21 , photographs of the nonionicsurfactant-ibuprofen-containing composition in the pH 1 solution, thenonionic surfactant-ibuprofen-containing composition in the solutionafter concentrated NaOH addition to raise the pH to pH 7, and thenonionic surfactant-ibuprofen-containing composition in the solutionafter concentrated HCl addition to lower the pH back to pH 1. Thephotographs show that the nonionic surfactant-ibuprofen-containingcomposition is immiscible in the pH 1 solutions and forms an emulsionwith an oil phase on top in the pH 7 solution. The nonionicsurfactant-ibuprofen-containing composition behaves similarly to the lowoleic acid-ibuprofen composition in the pH 7 solution, which also showedan emulsion with an oil layer on top. The nonionicsurfactant-ibuprofen-containing is fully reconstituted in the final pH 1solution, but now being a little less dense than the aqueous phase,where it was a little more dense in the pH 1 solution.

Uv Analysis of Nonionic Surfactant-Ibuprofen-Containing SamplesIBUPROFEN (IBU) UV Analysis of the NonionicSurfactant-Ibuprofen-Containing Composition

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as aspirin (ASA) is the onlygroup that absorbs UV light due to the presence of an aromatic ring. Thefollowing table includes the ASA UV results:

TABLE XXVII UV Ibuprofen (IBU) Phase Concentration Data in mg/mL andPercentages IBU in Oil IBU Aqueous IBU in Both IBU in Phase Phase PhasesOil Phase Solution (mg/mL) (mg/mL) (mg/mL) (%) pH 1 0.9825 0.0156 0.998198.44% pH 1-7 0.5033 0.2160 0.7193 69.96% pH 1-7-1 0.7369 0.0119 0.748798.42%

Referring now to FIG. 22 , the UV ibuprofen concentration values for thenonionic surfactant-ibuprofen-containing composition in the pH 1solutions and the pH 7 solution during the pH cycle experiment.Initially, essentially all of the ibuprofen is in the oil phase: 0.9825(98.44%) of ibuprofen in the oil phase compared to 0.0156 mg/mL (1.56%)in the aqueous phase. When the pH is raised to pH 7, the ibuprofenpartitions with 0.5033 mg/mL (69.96%) in the oil phase compared to0.2160 mg/mL (30.04%) in the aqueous phase. When the pH is lowered backto pH 1, a large amount of the ibuprofen is reabsorbed into the oilphase: 0.7369 (98.42%) in the oil phase compared to 0.0119 mg/mL (1.58%)in the aqueous phase.

Again, the inventors believe that this reconstitution and reabsorptionis a contributing factor to the superior GI safety of carriers of thisdisclosure. It appears that a sufficient amount of a free carboxylicacid in the carrier is responsible not only for the carrier's extremehydrophobicity as carrier is essentially immiscible in the initial pH 1aqueous solution, where the API, here ibuprofen, is primarily present inthe oil phase. The data also show that in the pH 7 solution, the API,ibuprofen here, is released into the aqueous phase, where almost equalamounts of ibuprofen are found in the two phases. The data also clearlyshow that the API, ibuprofen here, is reabsorbed into the carrier whenthe pH is lowered back to pH of about 1 reducing the amount of API inthe aqueous phase. These findings are consistent with the improved GIsafety of the compositions of this disclosure including an effectiveamount of free carboxylic acids.

Comparison of UV Ibuprofen Concentration Values for the Three IbuprofenCompositions

The three ibuprofen compositions were designed to determine whetherchanging the composition of the carrier would change the reconstitutionand API reabsorption properties of the matrix. To make the comparisoneasier, the UV ibuprofen (IBU) concentration values are tabulated below.

TABLE XXVIII UV Ibuprofen (IBU) Phase Concentration Percentage Data forthe Three IBU Compositions Standard High Oleic Acid Nonionic SurfactantComposition Composition Composition Oil Aqueous Oil Aqueous Oil AqueousSolution Phase Phase Phase Phase Phase Phase pH 1 99.97%  0.03% 98.69% 1.31% 98.44%  1.56% pH 1!7 52.56% 47.44% 62.68% 37.32% 69.96% 30.04% pH7!1 79.79% 20.21% 97.99%  2.01% 98.42%  1.58%

Additionally, referring now to FIG. 23 , the tabulated data is plotted.A review of the data in Table XV and shown in FIG. 23 clearly evidencethat the reconstitution and API reabsorption properties of the oilcarrier may be changed by changing the material composition of thecarrier. The standard composition includes a weight ratio of oleic acidto soybean oil is about 1:2, while the weight ratio of oleic acid tosoybean oil is about 1:1, a 50% increase on oleic acid and a 50%decrease on soybean oil. The consequences of the change in free fattyacid to triglyceride ratio caused a greater amount of the API to be inthe oil phase at pH 7 and a greater reabsorption of the API when the pHis adjusted from pH 7 back to pH 1. The increase in reabsorption wasabout 20%. A similar effect is seen when 5 wt. % of the oil is replacedby a nonionic surfactant also showing a 20% increase in APIreabsorption. Interestingly, the high oleic acid composition showedabout a 10% increase of the API in the oil phase at pH 7, while thesurfactant composition showed about a 15% increase of the API in the oilphase at pH 7. Thus, the carrier may be tailored to change APIpartitioning upon initial digestion (initial pH 1 data) and uponprogression into the duodenum (pH 7 solution) and finally, the amount ofAPI reabsorption during duodenal reflux.

Example 15 Whey Isolate Protein-Containing Composition Preparation andpH Cycle Testing

This example illustrates the preparation of a sample of a whey isolateprotein-containing composition subject to the duodenal reflux procedureoutlined above.

The whey isolate protein-containing composition included the followingingredients:

TABLE XXIX Quantity per Unit Quantity Ingredient (mg) (g) Whey IsolateProtein 20.25 20.26 Citric Acid Anhydrous Powder USP/EP 1.87 1.87Lecithin 3.95 3.98 Oleic Acid NF/EP 4.81 4.81 Soybean Oil-IV 10.41 10.42Total 41.29 41.34

Whey Isolate Protein-Containing Preparation

The whey isolate protein-containing composition was prepared as follows:

-   -   1. Screen citric acid and whey isolate protein (WIP) through a        40 mesh hand screen;    -   2. Add oleic acid, soybean oil, and lecithin into a 150 mL        beaker and heat the mixture while stirring with a stir bar on a        hot plate to until the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add whey isolate protein (WIP) to the mixture while stirring        with a Caframo mixer until the mixture achieves visual        uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Whey Protein Isolate-Containing Composition pH Cycle Test

The whey isolate protein-containing composition pH cycling was performedas follows:

-   -   1. Place 10 grams whey isolate protein in a 150 mL beaker        including 100 mL of a 0.1 N HCl solution having a pH of about 1;    -   2. Observe and photograph the whey isolate protein-containing        composition in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the whey isolate protein-containing        composition in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the whey isolate protein-containing        composition in the pH 1 solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Whey Isolate Protein-Containing Composition

Referring now to FIG. 24 , a photograph of the placebo and the wheyisolate protein-containing composition. The whey proteinisolate-containing composition was very thick. Visually, all three pHsolutions looked very similar. The whey isolate protein-containingcomposition did not hold a clearly observed form at the initial pH 1solution. The aqueous phases of all three solution, initial pH 1solution, pH 7 solution and final pH 1 solution, looked turbid. Somefoaming was noticed in the initial pH 1 solution. Looking at FIG. 25 ,three photographs are shown. The left two photographs shows the sampleof the whey isolate protein-containing composition after being added tothe simulated gastric fluid, initial pH 1 solution, where some foamingwas observed. The right photograph shows the sample of the whey isolateprotein-containing composition after concentrated NaOH was added to theinitial pH 1 solution to raise the pH to pH˜7. The oil phase is not asdistinct as in the case of NSAID, but there still does appear to be twophases. Looking at FIG. 26 , three photographs are shown. The leftphotograph shows the sample of the whey isolate protein-containingcomposition in the initial pH 1 solution; the middle photograph showsthe sample of the whey protein isolate-containing composition in the pH7 solution; and the right photograph shows the sample of the wheyisolate protein-containing composition after concentrated HCl was addedto lower the pH to pH˜1. In all three photographs the aqueous phaseappeared cloudy, and the oil phase appeared cloudy as well. Although theresults are not as pronounced as for NSAIDs, the data does showpartitioning, release in the pH 7 solution and some reabsorption in thefinal pH 1 solution. As noted above, the nature of the matrix is capableof changing the relative amounts of API in each phase at the twodifferent pH values, pH 1 and pH 7 suggesting that the matrix is capableof being optimized for different type of drugs or pharmaceutical thatevidence release and reabsorption dynamic in the same direction asobserved for the NSAIDs, or any small molecule pharmaceutical compoundthat does not include an amino group or an group that is easilyprotonated at pH values less than pH 3.

Uv Analysis of Whey Isolate Protein-Containing Samples Whey IsolateProtein UV Analysis

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as whey isolate proteinincludes amino acids that absorb UV light due to the presence of anaromatic ring. The following table includes the whey isolate protein UVconcentration results:

TABLE XXX UV Whey Isolate Protein (WIP) Concentration Data in mg/mL andPercentages WIP in Oil WIP Aqueous WIP in Both WIP in Oil Phase PhasePhases Phase Solution (mg/mL) (mg/mL) (mg/mL) (%) pH 1 0.24 0.33 0.5742.42 pH 1-7 0.08 0.49 0.57 14.24 pH 1-7-1 0.15 0.42 0.57 26.69

Referring now to FIG. 27 , a plot of UV percentage values of wheyisolate protein in both phases for the whey isolate protein-containingcomposition in the pH 1 solutions and the pH 7 solution during the pHcycle. In the initial pH 1 solution, about 60% of the whey isolateprotein (WIP) was in the aqueous phase and 40% in the oil phase. In thepH 7 solution, about 86% of the WIP was in the aqueous phase and 14% inthe oil phase. In the final pH 1 solution, about 73% was in the aqueousphase and 27% in the oil phase. While the results are not as pronouncedas in the case of aspirin and ibuprofen, the trends are similar andopposite of omeprazole suggesting that the matrix may be able to bemodified to reduce initial protein partitioning from the oil phase tothe aqueous phase in the stomach, increase release in the duodenum, andincrease reconstitution and reabsorption during duodenal reflux.

Referring now to FIG. 28 , a plot of a comparison of UV percentagevalues in the aqueous phase of aspirin, ibuprofen, whey isolate protein,and omeprazole compositions during a pH cycle. The plot shows thataspirin, ibuprofen and whey isolate protein behave in a similar manner,with the protein being absorbed to a higher extent in the aqueous phase,with omeprazole behaving the an opposite behavior compared to the otherAPIs.

Example 16. High Oleic Acid, Nonionic Surfactant Whey Isolate

Protein-Containing Composition Preparation and pH Cycle Testing

This example illustrates the preparation of a sample of a high oleicacid, nonionic surfactant (HA, NIS) whey isolate protein-containingcomposition subject to the duodenal reflux procedure outlined above.

The HA, NIS whey isolate protein-containing composition included thefollowing ingredients:

TABLE XXXI Quantity per Unit Quantity Ingredient (mg) (g) Whey IsolateProtein 20.25 20.27 Lecithin 3.95 3.97 Oleic Acid NF/EP 6.85 6.85Soybean Oil-IV 6.85 6.86 Nonionic Surfactant 1.52 1.52 (LAUROGLYCOL ™90)* Total 39.42 39.47 *LAUROGLYCOL ™ 90 (propylene glycol monolaurate)is a nonionic water-insoluble surfactant.

High Oleic Acid, Nonionic Surfactant Whey Isolate Protein-ContainingPreparation

The HA, NIS whey isolate protein-containing composition was prepared asfollows:

-   -   1. Screen citric acid and whey isolate protein (WIP) through a        40 mesh hand screen;    -   2. Add oleic acid, soybean oil, lecithin, and nonionic        surfactant (LAUROGLYCOL™ 90) into a 150 mL beaker and heat the        mixture while stirring with a stir bar on a hot plate to until        the mixture achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add whey protein isolate to the mixture while stirring with a        Caframo mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

HA, NIS Whey Isolate Protein-Containing Composition pH Cycle Test

The HA, NIS whey protein isolate-containing composition pH cycling wasperformed as follows:

-   -   1. Place 10 grams whey protein isolate in a 150 mL beaker        including 100 mL of a 0.1 N HCl solution having a pH of about 1;    -   2. Observe and photograph the HA, NIS whey protein        isolate-containing composition in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7;    -   5. Observe and photograph the HA, NIS whey protein        isolate-containing composition in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 1;    -   8. Observe and photograph the HA, NIS whey protein        isolate-containing composition in the pH 1 solution; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Whey Isolate Protein-Containing Composition

Referring now to FIG. 29 , three photographs of the HA, NIS whey proteinisolate-containing composition are shown. The left photograph shows thesample of the HA, NIS whey protein isolate-containing composition in theinitial pH 1 solution; the middle photograph shows the sample of the HA,NIS whey protein isolate-containing composition after the pH 1 solutionwas NaOH pH adjusted to pH 7; and the middle photograph shows the sampleof the HA, NIS whey protein isolate-containing composition after the pH7 solution was HCl pH adjusted back to pH 1. The whey proteinisolate-containing composition was thinner than the whey isolateprotein-containing composition of Example 15. Visually and similar tothe whey isolate protein-containing composition of Example 15, all threepH solutions looked very similar. The HA, NIS whey proteinisolate-containing composition also did not hold a clearly observed format the initial pH 1 solution. The aqueous phases of all three solution,initial pH 1 solution, pH 7 solution and final pH 1 solution, lookedturbid. Some foaming was noticed in the initial pH 1 solution.

Uv Analysis of Ha, Nis Whey Protein Isolate-Containing Samples WheyProtein Isolate UV Analysis

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis as whey isolate proteinincludes amino acids that absorb UV light due to the presence of anaromatic ring. The following table includes the whey protein isolate UVconcentration results:

TABLE XXXII UV Whey Isolate Protein (WIP) Concentration Data in mg/mLand Percentages WIP in Oil Phase WIP Aqueous Phase WIP in Both PhasesSolution (mg/mL) (mg/mL) (%) pH 1 0.48 0.09 83.45 pH 1-7 0.33 0.42 43.81pH 1-7-1 0.51 0.23 68.84

Referring now to FIG. 30 , a plot of UV percentage values for the wheyisolate protein from the HA, NIS whey isolate protein-containingcomposition in the pH 1 solutions and the pH 7 solution during the pHcycle. In the initial pH 1 solution, about 83.45% of the whey isolateprotein (WIP) was in the oil phase and 16.55% in the aqueous phase. Inthe pH 7 solution, about 43.81% of the WIP was in the oil phase and56.19% in the aqueous phase. In the final pH 1 solution, about 68.84% ofthe WIP was in the oil phase and 31.16% in the aqueous phase.

Referring now to FIG. 31 , a plot of a comparison of UV percentagevalues in the aqueous phase for the whey isolate protein-containingcomposition of Example 15 and the UV percentage values for the HA, NISwhey isolate protein-containing composition is shown. The plot clearlyshows that increasing the amount of oleic acid and adding a nonionicsurfactant lowered the amount of WIP in the aqueous of the initial pH 1solution, also lowers the amount of WIP released into the aqueous phaseat pH 7 and lowered the amount of WIP in the aqueous phase of the finalpH 1 solution. While the whey isolate protein has lower amount of WIPreleased at pH 7 compared to the whey isolate protein-containingcomposition of Example 15, the change in the matrix provides acomposition that reduces that amount of protein released in the initialpH 1 solution to less than 20% and near 40% reduction in WIP in theinitial pH 1 solution compared to the whey isolate protein-containingcomposition of Example 15. Additionally, the HA, NIS matrix showed agreater than 40% increase in reabsorption of the whey isolate proteincompared to the whey isolate protein-containing composition of ExampleClearly, the oil carrier or matrix may be modified to prepare a proteincomposition that releases minimally at pH 1, releases at a higher rateat pH 7 and have enhanced reconstitution and API reabsorptionproperties. Applying the matrix to proteins such as heparin and insulin,oral formulations of these proteins may be formulated. It should also berecognized that duodenum reflux involves a small fraction of thematerial entering the duodenum from the stomach and the API delivered tothe stomach will be absorbed from both the aqueous and oil phases in theduodenum. In fact, the oil phase may facilitate the absorption the APIin the duodenum or at least on hinder the transport of the API into theblood stream or lymphatic system depending on the transportationmechanism for the API entering the blood stream or the lymphatic system.

Referring now to FIG. 32 , a plot of a comparison of UV percentagevalues in the aqueous phase of aspirin, standard ibuprofen (StdIbuprofen), high oleic acid ibuprofen (HA Ibuprofen), nonionicsurfactant ibuprofen (NIS Ibuprofen), standard whey isolate protein (StdWIP), high oleic acid, nonionic surfactant whey isolate protein (HA, NISWIP), and omeprazole in the aqueous phase for their respectivecompositions is shown. The plot clearly shows that nonionic surfactantsgreatly modify API release amounts in the initial pH 1 solution, APIrelease amounts in the pH 7 solution, mimicking duodenum fluid, and inAPI reabsorption amounts in the final pH 1 solution. It should berecognized that the behavior of ibuprofen to the different matrices, theinventors fully expect aspirin to behavior in a similar manner toibuprofen. The inventors selected ibuprofen based on the fact ibuprofenis easier to analyze as it is not subject to hydrolysis like aspirin soonly a single compound must be analyzed by UV spectrometry.

Example 17. Nonionic Surfactant-Aspirin-Containing CompositionPreparation and pH Cycle Testing

This example illustrates the preparation of a sample of anaspirin-containing composition subject to the duodenal reflux procedureoutlined above, wherein the carrier includes 9 wt. % citric acid (dryingagent), 15 wt. % lecithin, 15 wt. % nonionic surfactant (LAUROGLYCOL™ 20wt. % oleic acid, and 41 wt. % soybean oil.

The aspirin-containing composition included the following ingredients:

TABLE XXXIII Quantity per Unit Quantity Ingredient (mg) (g) Aspirin(ASA) 20.25 20.25 Citric Acid Anhydrous Powder USP/EP 1.89 1.89 Lecithin3.16 3.16 Oleic Acid NF/EP 4.21 4.22 Soybean Oil-IV 8.63 8.64 NonionicSurfactant 3.16 3.17 (LAUROGLYCOL ™ 90) Total 41.30 41.33

Nonionic Surfactant-Aspirin-Containing Composition Preparation Procedure

The aspirin-containing composition was prepared as follows:

-   -   1. Screen citric acid and aspirin (ASA) through a 40 mesh hand        screen;    -   2. Add oleic acid, soybean oil, lecithin, and nonionic        surfactant into a 150 mL beaker and heat the mixture while        stirring with a stir bar on a hot plate to until the mixture        achieves visual uniformity;    -   3. Add citric acid to the mixture while stirring with the stir        bar on the hot plate until the mixture achieves visual        uniformity;    -   4. Add aspirin to the mixture while stirring with a Caframo        mixer until the mixture achieves visual uniformity; and    -   5. Continue stirring the mixture during testing to maintain        uniformity.

Aspirin-Containing Composition pH Cycle Test Procedure

The aspirin-containing composition pH cycle test was performed asfollows:

-   -   1. Place 10 g of the nonionic surfactant-aspirin-containing        composition in a 150 mL beaker containing 100 mL of a 0.1 N HCl        solution having a pH of about 1, simulated gastric fluid;    -   2. Observe and photograph the nonionic        surfactant-aspirin-containing composition in the pH 1 solution;    -   3. Collect a sample of the oil phase and the aqueous phase from        the pH 1 solution for UV analysis;    -   4. Add concentrated NaOH to the beaker with stirring while        monitoring the pH with a pH meter until the pH is about 7,        simulated duodenal fluid;    -   5. Observe and photograph the nonionic        surfactant-aspirin-containing composition in the pH 7 solution;    -   6. Collect a sample of the oil phase and aqueous phase from the        pH 7 solution for UV analysis;    -   7. Add concentrated HCl to the beaker with stirring while        monitoring the pH with the pH meter until the pH is about 1;    -   8. Observe and photograph the nonionic        surfactant-aspirin-containing composition in the pH 1 solution,        back to simulated gastric fluid; and    -   9. Collect a sample of the oil phase and aqueous phase from the        pH 1 solution for UV analysis.

Photographs of Control and Nonionic Surfactant-Aspirin-ContainingCompositions Photographs of Mixing, pH Monitoring, and TemperatureMonitoring

Referring now to FIG. 33 , photographs are shown of the controlcomposition compared to the nonionic surfactant-aspirin-containingcomposition.

Photographs of Nonionic Surfactant-Aspirin-Containing Composition Duringa pH Cycle

Referring now to FIG. 34 , photographs show a sample of the nonionicsurfactant-aspirin-containing composition in an initial pH 1 solution(left photograph), in a pH 7 solution after concentrated NaOH additionto the initial pH 1 solution (middle photograph), and in a final pH 1solution after concentrated HCl addition to the pH 7 aqueous solution(right photograph). The nonionic surfactant-aspirin-containingcomposition is clearly immiscible in the initial pH 1 solution and isdenser than the aqueous phase. When the pH is raised to pH 7, a changein the look of the control composition may be seen—compare the far leftphotograph to the middle photograph. At pH 7, the nonionicsurfactant-aspirin-containing composition appears to include a top oilphase and a cloudy aqueous phase, likely an emulsion. When the pH of thepH 7 solution is lowered back to pH 1, the aqueous phase clarifies,while the oil phase now appears similar to its starting form.

Uv Analysis of Nonionic Surfactant-Aspirin-Containing Samples Aspirin(ASA) UV Analysis

The samples taken from the oil and aqueous phases during the pH cyclingwere analyzed using UV spectral analysis. Aspirin (ASA) is the onlyingredient in the sample that includes an aromatic ring and has adistinct UV absorption. UV spectral analysis was used to determine theconcentration of ASA in the UV detection samples. The following tableincludes ASA concentrations as determined by UV spectral analysis:

TABLE XXXIV UV Aspirin (ASA) Phase Concentration Data in mg/ml ASA inOil Phase ASA Aqueous ASA in Oil Solution (mg/mL) Phase (mg/mL) Phase(%) pH 1 0.77 0.03 96.69 pH 1-7 0.20 0.24 45.41 pH 1-7-1 0.98 0.04 96.06

Referring now to FIG. 35 , a plot of the UV aspirin (ASA) concentrationvalues (mg/mL) for the oil phase and the aqueous phase from the sampleof the nonionic surfactant-aspirin-containing composition during the pHcycle experiment is shown. Initially, the ASA (aspirin) is almostexclusively in the oil phase with 0.77 mg/mL (96.69%) in the oil phasecompared to 0.03 mg/mL (3.31%) in the aqueous phase. When the pH israised to pH 7, the ASA (aspirin) is present in the aqueous phase to agreater degree than in the oil phase with 0.24 mg/mL (54.59%) in theaqueous phase compared to 0.20 mg/mL (45.41%) in the oil phase. When thepH is lowered back to pH 1, a large amount of the ASA (aspirin) from theaqueous phase was almost completely reabsorbed into the oil phase with0.98 mg/mL (96.06%) in the oil phase compared to 0.04 mg/mL (3.94%) inthe aqueous phase. Clearly, the carrier of this disclosure may betailored to significantly decrease the amount of API releases in thestomach and significantly increase the amount of API reabsorbed into thecarrier during duodenal reflux, a completely unexpected result.

Referring now to FIG. 36 , a plot comparing the UV aspirin (ASA)percentage concentration values for the aqueous phase of theaspirin-containing composition of Example 10 and the aspirin (ASA)percentage concentration values for the aqueous phase of the nonionicsurfactant-aspirin-containing composition of this Example 17 during thepH cycle experiment is shown. The addition of the nonionic surfactant tothe aspirin-containing composition of Example 10 resulted in a 77.78%decrease in the amount of aspirin (˜18% to ˜4%) in the initial pH 1aqueous phase and a 86.21% increase in the amount of aspirin (˜30% to˜4%) reabsorbed in the final pH 1 aqueous phase during the pH cycle.These results, as in the ibuprofen and whey isolate protein examples,are significant and unexpected as there is no guidance from the priorart that the addition of a nonionic surfactant would result in such asmarked increase in concentration of the API in the oil phase in theinitial pH 1 solution and the marked increase in the concentration ofthe API in the oil phase in the final pH 1 solution.

Referring now to FIG. 37 , a plot of a comparison of UV percentagevalues in the aqueous phase of standard aspirin (Std ASA), nonionicsurfactant aspirin (NIS ASA), standard ibuprofen (Std Ibuprofen), higholeic acid ibuprofen (HA Ibuprofen), nonionic surfactant ibuprofen (NISIbuprofen), standard whey isolate protein (Std WIP), high oleic acid,nonionic surfactant whey isolate protein (HA, NIS WIP), and omeprazolein the aqueous phase for their respective compositions is shown. Theplot clearly shows that nonionic surfactants greatly modify API releaseamounts in the initial pH 1 solution, API release amounts in the pH 7solution, mimicking duodenum fluid, and in API reabsorption amounts inthe final pH 1 solution. The data clearly shows that the carrier may betailored to significantly reduce the amount of API reduced in theinitial pH 1 solution and significantly increase the amount of APIreabsorbed in the final pH 1 solution.

All references cited herein are incorporated by reference. Although thedisclosure has been disclosed with reference to its preferredembodiments, from reading this description those of skill in the art mayappreciate changes and modification that may be made which do not departfrom the scope and spirit of the disclosure as described above andclaimed hereafter.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds, or compositions, which can ofcourse vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof, inclusive of the endpoints. Anylisted range can be easily recognized as sufficiently describing andenabling the same range being broken down into at least equal halves,thirds, quarters, fifths, tenths, etc. As a non-limiting example, eachrange discussed herein can be readily broken down into a lower third,middle third and upper third, etc. As will also be understood by oneskilled in the art all language such as “up to,” “at least,” “greaterthan,” “less than,” and the like, include the number recited and referto ranges which can be subsequently broken down into subranges asdiscussed above. Finally, as will be understood by one skilled in theart, a range includes each individual member.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

Embodiment 1. A pharmaceutical carrier composition comprising:

-   -   (a) a non-aqueous pH dependent release system; and    -   (b) a non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system,    -   wherein:        -   (i) the carrier composition has a low pH form and a high pH            form;        -   (ii) the carrier composition is formulated to release one or            more biologically active agents minimally from a low pH form            and maximally from a high pH form due to the non-aqueous pH            dependent release system;        -   (iii) the carrier composition is formulated to either            reassemble into the low pH form or assembly into a new low            pH form due to the non-aqueous pH dependent            reassembly/assembly and reabsorption/absorption system; and        -   (iv) the carrier is formulated to either reabsorb the one or            more biologically active agents in its reassembled form or            absorb the one or more biologically active agents in the            newly assembled form.

Embodiment 2. The composition of Embodiment 1, wherein the non-aqueouspH dependent reassembly/assembly and reabsorption/absorption systemcomprises:

-   -   (a) one or more polyacids,    -   (b) one or more polymers including a plurality of carboxylic        acid moieties,    -   (c) one or more surfactants,    -   (d) one or more water insoluble oligomers,    -   (e) one or more water insoluble polymers, and any combination        thereof.

Embodiment 3. The composition of Embodiment 1 or 2, wherein the pHdependent release system comprises at least 5 wt. % of a carboxylic acidhaving at least 8 carbon atoms.

Embodiment 4. The composition of Embodiment 3, wherein the pH dependentrelease system comprises at least 8 wt. % of a carboxylic acid having atleast 8 carbon atoms.

Embodiment 5. The composition of Embodiment 4, wherein the pH dependentrelease system comprises at least 10 wt. % of a carboxylic acid havingat least 8 carbon atoms.

Embodiment 6. The composition of Embodiment 5, wherein the pH dependentrelease system comprises at least 15 wt. % of a carboxylic acid havingat least 8 carbon atoms.

Embodiment 7. The composition of any one of Embodiments 1 to 6, whereinthe carboxylic acid having at least 8 carbon atoms is a monocarboxylicacid.

Embodiment 8. The composition of any one of Embodiments 1 to 7, whereinthe pH dependent release system comprises a carboxylic acid having atleast 8 carbon atoms with a low melting point.

Embodiment 9. The composition of any one of Embodiments 1 to 8, whereinthe pH dependent release system comprises a carboxylic acid having atleast 8 carbon atoms with a medium melting point.

Embodiment 10. The composition of any one of Embodiments 1 to 9, whereinthe pH dependent release system comprises a carboxylic acid having atleast 8 carbon atoms with a high melting point.

Embodiment 11. The composition of any one of Embodiments 1 to 10,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more poly acids.

Embodiment 12. The composition of Embodiment 11, wherein the one or morepolyacids comprises a biocompatible fatty poly acid.

Embodiment 13. The composition of Embodiment 11 or 12, wherein the oneor more polyacids comprise Glutaric acid (GA).

Embodiment 14. The composition of any one of Embodiments 11 to 13,wherein the one or more polyacids comprise EUDRAGIT® L (EL).

Embodiment 15. The composition of any one of Embodiments 11 to 14,wherein the one or more polyacids comprise EUDRAGIT® E (EE).

Embodiment 16. The composition of any one of Embodiments 11 to 15,wherein the one or more polyacids comprise Hypromellose Phtalate(HPMC-P).

Embodiment 17. The composition of any one of Embodiments 1 to 16,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more polymers includinga plurality of carboxylic acid moieties.

Embodiment 18. The composition of any one of Embodiments 1 to 17,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more surfactants.

Embodiment 19. The composition of Embodiment 18, wherein the one or moresurfactants comprise a nonionic surfactant.

Embodiment 20. The composition of Embodiment 18 or 19, wherein the oneor more surfactants comprise sorbitan trioleate (STO).

Embodiment 21. The composition of any one of Embodiments 18 to 20,wherein the one or more surfactants comprise sorbitan monooleate.

Embodiment 22. The composition of any one of Embodiments 18 to 21,wherein the one or more surfactants comprise sorbitan tristearate.

Embodiment 23. The composition of any one of Embodiments 1 to 22,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more water insolubleoligomers.

Embodiment 24. The composition of any one of Embodiments 1 to 23,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more water insolublepolymers.

Embodiment 25. The composition of any one of Embodiments 1 to 24,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises a reconstitution agent with alow melting point.

Embodiment 26. The composition of any one of Embodiments 1 to 25,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises a reconstitution agent with amedium melting point.

Embodiment 27. The composition of any one of Embodiments 1 to 26,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises a reconstitution agent with ahigh melting point.

Embodiment 28. The composition of any one of Embodiments 1 to 27,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 10 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 90 wt. %.

Embodiment 29. The composition of any one of Embodiments 1 to 28,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 20 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 80 wt. %.

Embodiment 30. The composition of any one of Embodiments 1 to 29,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 30 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 70 wt. %.

Embodiment 31. The composition of any one of Embodiments 1 to 30,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 40 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 60 wt. %.

Embodiment 32. The composition of any one of Embodiments 1 to 31,wherein the non-aqueous pH dependent release system comprises:

-   -   (a) at least 15 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms,    -   (b) at least 20 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms, or    -   (c) at least 30 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms.

Embodiment 33. The composition of any one of Embodiments 1 to 32,wherein the non-aqueous pH dependent release system comprises:

-   -   (a) at least 15 wt. % of a mixture of (i) one or more low        melting point monocarboxylic acids, (ii) one or more medium        melting point monocarboxylic acids, (iii) one or more high        melting point monocarboxylic acids, or (iv) any combination        thereof, and    -   (b) wherein:        -   (i) the low melting point monocarboxylic acids have melting            point temperatures less than or equal to room temperature,        -   (ii) the medium melting point monocarboxylic acids have            melting point temperatures greater than room temperature and            less than or equal to a body temperature of a mammal, or a            human, and        -   (iii) the high melting point monocarboxylic acids have            melting point temperatures above the body temperature of a            mammal, or a human.

Embodiment 34. The composition of any one of Embodiments 1 to 33,wherein the non-aqueous pH dependent release system further comprisesone or more neutral lipids.

Embodiment 35. The composition of Embodiment 34, wherein the one or moreneutral lipids comprise a fatty acid ester.

Embodiment 36. The composition of Embodiment 35, wherein the fatty acidester is a fatty acid methyl ester.

Embodiment 37. The composition of Embodiment 35, wherein the fatty acidmethyl ester is methyl linolenate.

Embodiment 38. The composition of Embodiment 35, wherein the fatty acidmethyl ester is methyl oleate.

Embodiment 39. The composition of Embodiment 35, wherein the fatty acidmethyl ester is methyl palmitate.

Embodiment 40. The composition of any one of Embodiments 33 to 39,wherein the non-aqueous pH dependent release system further comprisesone or more low melting point neutral lipids.

Embodiment 41. The composition of any one of Embodiments 33 to 40,wherein the non-aqueous pH dependent release system further comprisesone or more medium melting point neutral lipids.

Embodiment 42. The composition of any one of Embodiments 33 to 41,wherein the non-aqueous pH dependent release system further comprisesone or more high melting point neutral lipids.

Embodiment 43. The composition of any one of Embodiments 1 to 42,further comprising less than 10 wt. % of one or more selected from (1)fatty acid salts, (2) secondary complexing agents, (3) protectiveagents, (4) excipients, (5) adjuvants, (6) drying agents, (7)antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders.

Embodiment 44. The carrier composition according to any one ofEmbodiments 1 to 43, wherein the composition comprises less than 10 wt.% zwittterionic phospholipid.

Embodiment 45. A pharmaceutical composition comprising:

-   -   (a) a carrier composition according to any one of Embodiments 1        to 44; and    -   (b) one or more biologically active agents,    -   wherein a weight ratio of the carrier composition to the one or        more biologically active agents is between about 10:1 and about        1:2.

Embodiment 46. The pharmaceutical composition of Embodiment 45, whereinthe one or more biologically active agents is suspended in the carriercomposition.

Embodiment 47. The pharmaceutical composition of Embodiment 45 or 46,wherein the one or more biologically active agents are crystalline solidparticles.

Embodiment 48. The pharmaceutical composition of any one of Embodiments45 to 47, wherein the biologically active agent comprises at least oneagent selected from the group consisting of an acid-labilepharmaceutical agent, an anti-depressant, an anti-diabetic agent, ananti-epileptic agent, an anti-fungal agent, an anti-malarial agent, ananti-muscarinic agent, an anti-neoplastic agent, an immunosuppressant,an anti-protozoal agent, an anti-tussive, a neuroleptics, abeta-blocker, a cardiac inotropic agent, a corticosteroid, ananti-parkinsonian agent, a gastrointestinal agent, histamine, ahistamine receptor antagonist, a keratolytic, a lipid regulating agent,a muscle relaxant, a nitrate, an anti-anginal agent, a nutritionalagent, an opioid analgesic, a sex hormone, a stimulant, a nutraceutical,a peptide, a protein, a therapeutic protein, a nucleoside, a nucleotide,DNA, RNA, a glycosaminoglycan, an acid-labile drug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carb oxyli c acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amideranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.

Embodiment 49. The pharmaceutical composition of any one of Embodiments45 to 48, wherein the one or more biologically active agents ishydrophobic.

Embodiment 50. The pharmaceutical composition of any one of Embodiments45 to 49, wherein the one or more biologically active agents includes anacid labile drug.

Embodiment 51. The pharmaceutical composition of Embodiment 50, whereinthe acid-labile drug is selected from the group consisting of heparin,insulin, erythropoietin, pancreatin, lansoprazole, omeprazole,pantoprazole, rabeprazole, penicillin salts, benzathine penicillin,polymyxin, sulphanilamide, and erythromycin.

Embodiment 52. The pharmaceutical composition of any one of Embodiments45 to 48, wherein the one or more biologically active agents includes anon-steroidal anti-inflammatory agent (NSAID).

Embodiment 53. The pharmaceutical composition of Embodiment 52, whereinthe NSAID is selected from the group consisting of ibuprofen, piroxicam,salicylate, aspirin, naproxen, indomethacin, diclofenac, mefenamic acid,COX2 inhibitors, and any mixture thereof.

Embodiment 54. The pharmaceutical composition of Embodiment 52, whereinthe NSAID is selected from the group consisting of aspirin, naproxen,indomethacin and mefenamic acid.

Embodiment 55. The pharmaceutical composition of Embodiment 52, whereinthe NSAID is aspirin.

Embodiment 56. A pharmaceutical carrier composition comprising:

-   -   (a) a non-aqueous pH dependent release system; and    -   (b) a non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system,    -   wherein:        -   (i) the carrier composition has a low pH form and a high pH            form;        -   (ii) the carrier composition is formulated to release one or            more biologically active agents minimally from a low pH form            and maximally from a high pH form due to the non-aqueous pH            dependent release system;        -   (iii) the carrier composition is formulated to either            reassemble into the low pH form or assembly into a new low            pH form due to the non-aqueous pH dependent            reassembly/assembly and reabsorption/absorption system; and        -   (iv) the carrier composition is formulated to either            reabsorb the one or more biologically active agents in its            reassembled form or absorb the one or more biologically            active agents in the newly assembled form.

Embodiment 57. The composition of Embodiment 56, wherein the non-aqueouspH dependent reassembly/assembly and reabsorption/absorption systemcomprises one or more nonionic surfactants.

Embodiment 58. The composition of Embodiment 57, wherein the one or morenonionic surfactants are present in the composition in an amount ofabout 0.05 wt. % to about 20 wt. %.

Embodiment 59. The composition of Embodiments 57 or 58, wherein the oneor more nonionic surfactants comprise an ethylene glycol mono fatty acidester, a propylene glycol mono fatty acid ester, or a combination of twoor more thereof.

Embodiment 60. The composition of Embodiments 57 or 58, wherein the oneor more nonionic surfactants comprise one or more selected from sorbitanmono, di, and tri fatty acid esters.

Embodiment 61. The composition of Embodiments 57 or 58, wherein the oneor more nonionic surfactants comprise propylene glycol monolaurate.

Embodiment 62. The composition of Embodiments 57 or 58, wherein the oneor more nonionic surfactants comprise sorbitan trioleate (STO), sorbitanmonooleate, or sorbitan tristearate, or a combination thereof.

Embodiment 63. The composition of any one of Embodiments 56 to 62,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more zwittterionicsurfactants.

Embodiment 64. The composition of Embodiment 63, wherein the one or morezwittterionic surfactants comprise one or more zwittterionicphospholipids.

Embodiment 65. The composition of Embodiments 63 or 64, wherein the oneor more zwitterionic surfactants comprise phosphatidic acid,phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,phosphatidylinositol, phosphatidylinositol phosphate,phosphatidylinositol bisphosphate, phosphatidylinositol triphosphate,ceramide phosphorylcholine, ceramide phosphorylethanolamine, ceramidephosphorylglycerol, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilinoleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, or a combination of two or more thereof.

Embodiment 66. The composition of any one of Embodiments 63 to 65,wherein the one or more zwitterionic surfactants comprise lecithin.

Embodiment 67. The composition of any one of Embodiments 63 to 66,wherein the one or more zwittterionic surfactants are present in thecomposition in an amount of at least about 10 wt. %.

Embodiment 68. The composition of any one of Embodiments 63 to 66,wherein the one or more zwitterionic surfactants are present in thecomposition in an amount of about 5 wt. % to about 25 wt. %.

Embodiment 69. The composition of any one of Embodiments 56 to 68,wherein the pH dependent release system comprises a carboxylic acidhaving at least 8 carbon atoms.

Embodiment 70. The composition of Embodiment 69, wherein the carboxylicacid having at least 8 carbon atoms is present in the composition in anamount of at least about 5 wt. %.

Embodiment 71. The composition of Embodiment 69, wherein the carboxylicacid having at least 8 carbon atoms is present in the composition in anamount of at least about 10 wt. %.

Embodiment 72. The composition of Embodiment 69, wherein the carboxylicacid having at least 8 carbon atoms is present in the composition in anamount of at least about 15 wt. %.

Embodiment 73. The composition of Embodiment 69, wherein the carboxylicacid having at least 8 carbon atoms is present in the composition in anamount of at least about 20 wt. %.

Embodiment 74. The composition of Embodiment 69, wherein the carboxylicacid having at least 8 carbon atoms is present in the composition in anamount of about 5 wt. % to about 50 wt. %.

Embodiment 75. The composition of any one of Embodiments 69 to 74,wherein the carboxylic acid having at least 8 carbon atoms is amonocarboxylic acid.

Embodiment 76. The composition of any one of Embodiments 69 to 75,wherein the carboxylic acid having at least 8 carbon atoms is selectedfrom the group consisting of as octenoic acid, decenoic acid,decadienoic acid, lauroleic acid, laurolinoleic acid, myristovaccenicacid, myristolinoleic acid, myristolinolenic acid, palmitolinolenicacid, palmitidonic acid, α-linolenic acid, stearidonic acid,dihomo-α-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid,clupanodonic acid, docosahexaenoic acid,9,12,15,18,21-tetracosapentaenoic acid,6,9,12,15,18,21-tetracosahexaenoic acid, myristoleic acid,palmitovaccenic acid, α-eleostearic acid, β-eleostearic acid, punicicacid, 7,10,13-octadecatrienoic acid, 9,12,15-eicosatrienoic acid,β-eicosatetraenoic acid, 8-tetradecenoic acid, 12-octadecenoic acid,linoleic acid, linolelaidic acid, γ-linolenic acid, calendic acid,pinolenic acid, dihomo-linoleic acid, dihomo-γ-linolenic acid,arachidonic acid, adrenic acid, osbond acid, palmitoleic acid, vaccenicacid, rumenic acid, paullinic acid, 7,10,13-eicosatrienoic acid, oleicacid, elaidic acid, gondoic acid, erucic acid, nervonic acid,8,11-eicosadienoic acid, mead acid, sapienic acid, gadoleic acid,4-hexadecenoic acid, petroselinic acid, and 8-eicosenoic acid, or acombination of two or more thereof.

Embodiment 77. The composition of any one of Embodiments 56 to 76,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system further comprises:

-   -   (a) one or more polyacids,    -   (b) one or more water insoluble oligomers,    -   (c) one or more water insoluble polymers, or    -   (d) any combination thereof.

Embodiment 78. The composition of Embodiment 77, wherein the one or morepolyacids comprise a biocompatible fatty poly acid.

Embodiment 79. The composition of Embodiment 77, wherein the one or morepolyacids comprise glutaric acid (GA), poly(methacrylic acid-co-methylmethacrylate), or hypromellose phthalate (HPMC-P), or a combination oftwo or more thereof.

Embodiment 80. The composition of any one of Embodiments 77 to 79,wherein the one or more polyacids are present in the composition in anamount of about 1 wt. % to about 10 wt. %.

Embodiment 81. The composition of any one of Embodiments 77 to 80,wherein the one or more water insoluble oligomers comprise low molecularweight poly(hexyl substituted lactides) (PHLA), low molecular weightpolyethylene, polyvinyl chloride, ethyl cellulose, or acrylate polymersand copolymers thereof, or a combination of two or more thereof.

Embodiment 82. The composition of any one of Embodiments 77 to 81,wherein the one or more water insoluble oligomers are present in thecomposition in an amount of about 1 wt. % to about 5 wt. %.

Embodiment 83. The composition of any one of Embodiments 77 to 82,wherein the one or more water insoluble polymers comprise a copolymer ofethyl acrylate and methyl methacrylate, lactide-coglycolide, cellulose,or ethyl cellulose, or a combination of two or more thereof.

Embodiment 84. The composition of any one of Embodiments 77 to 83,wherein the one or more water insoluble polymers are present in thecomposition in an amount of about 1 wt. % to about 5 wt. %.

Embodiment 85. The composition of any one of Embodiments 56 to 84,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 10 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 90 wt. %.

Embodiment 86. The composition of any one of Embodiments 56 to 84,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 20 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 80 wt. %.

Embodiment 87. The composition of any one of Embodiments 56 to 84,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 30 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 70 wt. %.

Embodiment 88. The composition of any one of Embodiments 56 to 84,wherein:

-   -   (a) the non-aqueous pH dependent release system is present in an        amount between 40 wt. % and 95 wt. %; and    -   (b) the non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system is present in an amount between        about 5 wt. % and 60 wt. %.

Embodiment 89. The composition of any one of Embodiments 56 to 88,wherein the non-aqueous pH dependent release system comprises:

-   -   (a) at least 15 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms,    -   (b) at least 20 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms, or    -   (c) at least 30 wt. % of one or more monocarboxylic acids having        at least 8 carbon atoms.

Embodiment 90. The composition of any one of Embodiments 56 to 89,wherein the non-aqueous pH dependent release system comprises:

-   -   (a) at least 15 wt. % of a mixture of (i) one or more low        melting point monocarboxylic acids, (ii) one or more medium        melting point monocarboxylic acids, (iii) one or more high        melting point monocarboxylic acids, or (iv) any combination        thereof, and    -   (b) wherein:        -   (i) the low melting point monocarboxylic acids have melting            point temperatures less than or equal to room temperature,        -   (ii) the medium melting point monocarboxylic acids have            melting point temperatures greater than room temperature and            less than or equal to a body temperature of a mammal, or a            human, and        -   (iii) the high melting point monocarboxylic acids have            melting point temperatures above the body temperature of a            mammal, or a human.

Embodiment 91. The composition of any one of Embodiments 56 to 90,wherein the non-aqueous pH dependent release system further comprisesone or more neutral lipids.

Embodiment 92. The composition of Embodiment 91, wherein the one or moreneutral lipids comprise one or more biocompatible oils.

Embodiment 93. The composition of Embodiment 92, wherein the one or morebiocompatible oils comprise peanut oil, canola oil, avocado oil,safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin A,vitamin D, vitamin E, animal oils, fish oils, or krill oil, or acombination of two or more thereof.

Embodiment 94. The composition of Embodiment 91, wherein the one or moreneutral lipids comprise a fatty acid ester.

Embodiment 95. The composition of Embodiment 94, wherein the fatty acidester is a fatty acid methyl ester.

Embodiment 96. The composition of Embodiment 95, wherein the fatty acidmethyl ester is methyl linolenate, methyl oleate, or methyl palmitate,or a combination of thereof.

Embodiment 97. The composition of any one of Embodiments 91 to 96,wherein the one or more neutral lipids are present in the composition inan amount of about 30 wt. % to about 75 wt. %.

Embodiment 98. The composition of any one of Embodiments 56 to 90,wherein the non-aqueous pH dependent release system further comprisesone or more low melting point neutral lipids.

Embodiment 99. The composition of any one of Embodiments 56 to 90,wherein the non-aqueous pH dependent release system further comprisesone or more medium melting point neutral lipids.

Embodiment 100. The composition of any one of Embodiments 56 to 90,wherein the non-aqueous pH dependent release system further comprisesone or more high melting point neutral lipids.

Embodiment 101. The composition of any one of Embodiments 56 to 100,further comprising less than 10 wt. % of one or more selected from (1)fatty acid salts, (2) secondary complexing agents, (3) protectiveagents, (4) excipients, (5) adjuvants, (6) drying agents, (7)antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders.

Embodiment 102. A pharmaceutical composition comprising, consistingessentially of, or consisting of:

-   -   (a) a carrier composition according to any one of Embodiments 56        to 101; and    -   (b) one or more biologically active agents,    -   wherein a weight ratio of the carrier composition to the one or        more biologically active agents is between about 10:1 and about        1:2.

Embodiment 103. The pharmaceutical composition of Embodiment 102,wherein the one or more biologically active agents is suspended in thecarrier composition.

Embodiment 104. The pharmaceutical composition of Embodiments 102 or103, wherein the one or more biologically active agents are crystallinesolid particles.

Embodiment 105. The pharmaceutical composition of any one of Embodiments102 to 104, wherein the biologically active agent comprises at least oneagent selected from the group consisting of an acid-labilepharmaceutical agent, an anti-depressant, an anti-diabetic agent, ananti-epileptic agent, an anti-fungal agent, an anti-malarial agent, ananti-muscarinic agent, an anti-neoplastic agent, an immunosuppressant,an anti-protozoal agent, an anti-tussive, a neuroleptics, abeta-blocker, a cardiac inotropic agent, a corticosteroid, ananti-parkinsonian agent, a gastrointestinal agent, histamine, ahistamine receptor antagonist, a keratolytic, a lipid regulating agent,a muscle relaxant, a nitrate, an anti-anginal agent, a non-steroidalanti-inflammatory agent, a nutritional agent, an opioid analgesic, a sexhormone, a stimulant, a nutraceutical, a peptide, a protein, atherapeutic protein, a nucleoside, a nucleotide, DNA, RNA, aglycosaminoglycan, an acid-labile drug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amideranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.

Embodiment 106. The pharmaceutical composition of any one of Embodiments102 to 105, wherein the one or more biologically active agents ishydrophobic.

Embodiment 107. The pharmaceutical composition of any one of Embodiments102 to 106, wherein the one or more biologically active agents includesan acid labile drug.

Embodiment 108. The pharmaceutical composition of Embodiment 107,wherein the acid-labile drug is selected from the group consisting ofheparin, insulin, erythropoietin, pancreatin, lansoprazole, omeprazole,pantoprazole, rabeprazole, penicillin salts, benzathine penicillin,polymyxin, sulphanilamide, and erythromycin.

Embodiment 109. The pharmaceutical composition of any one of Embodiments102 to 105, wherein the one or more biologically active agents includesa non-steroidal anti-inflammatory agent (NSAID).

Embodiment 110. The pharmaceutical composition of Embodiment 109,wherein the NSAID is selected from the group consisting of ibuprofen,piroxicam, salicylate, aspirin, naproxen, indomethacin, diclofenac,mefenamic acid, COX2 inhibitors, and any mixture thereof.

Embodiment 111. The pharmaceutical composition of Embodiment 110,wherein the NSAID is selected from the group consisting of aspirin,naproxen, indomethacin and mefenamic acid.

Embodiment 112. The pharmaceutical composition of Embodiment 110,wherein the NSAID is aspirin.

Embodiment 113. A pharmaceutical carrier composition consistingessentially of or consisting of:

-   -   (a) a non-aqueous pH dependent release system;    -   (b) a non-aqueous pH dependent reassembly/assembly and        reabsorption/absorption system; and    -   (c) optionally less than 10 wt. % of one or more selected        from (1) fatty acid salts, (2) secondary complexing agents, (3)        protective agents, (4) excipients, (5) adjuvants, (6) drying        agents, (7) antioxidants, (8) preservatives, (9) chelating        agents, (10) viscomodulators, (11) tonicifiers, (12) flavorants        and taste masking agents, (13) colorants, (14) odorants, (15)        opacifiers, (16) suspending agents, and (17) binders;    -   wherein:        -   (i) the carrier composition has a low pH form and a high pH            form;        -   (ii) the carrier composition is formulated to release one or            more biologically active agents minimally from a low pH form            and maximally from a high pH form due to the non-aqueous pH            dependent release system;        -   (iii) the carrier composition is formulated to either            reassemble into the low pH form or assembly into a new low            pH form due to the non-aqueous pH dependent            reassembly/assembly and reabsorption/absorption system; and        -   (iv) the carrier composition is formulated to either            reabsorb the one or more biologically active agents in its            reassembled form or absorb the one or more biologically            active agents in the newly assembled form.

Embodiment 114. The composition of Embodiment 113, wherein thenon-aqueous pH dependent reassembly/assembly and reabsorption/absorptionsystem comprises one or more nonionic surfactants.

Embodiment 115. The composition of Embodiment 114, wherein the one ormore nonionic surfactants are present in the composition in an amount ofabout 0.05 wt. % to about 20 wt. %.

Embodiment 116. The composition of Embodiments 114 or 115, wherein theone or more nonionic surfactants comprise an ethylene glycol mono fattyacid ester, a propylene glycol mono fatty acid ester, or a combinationof two or more thereof.

Embodiment 117. The composition of Embodiments 114 or 115, wherein theone or more nonionic surfactants comprise one or more selected fromsorbitan mono, di, and tri fatty acid esters.

Embodiment 118. The composition of Embodiments 114 or 115, wherein theone or more nonionic surfactants comprise propylene glycol monolaurate.

Embodiment 119. The composition of Embodiments 114 or 115, wherein theone or more nonionic surfactants comprise sorbitan trioleate (STO),sorbitan monooleate, or sorbitan tristearate, or a combination thereof.

Embodiment 120. The composition of any one of Embodiments 113 to 119,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprises one or more zwittterionicsurfactants.

Embodiment 121. The composition of Embodiment 120, wherein the one ormore zwittterionic surfactants comprise one or more zwittterionicphospholipids.

Embodiment 122. The composition of Embodiments 120 or 121, wherein theone or more zwitterionic surfactants comprise phosphatidic acid,phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,phosphatidylinositol, phosphatidylinositol phosphate,phosphatidylinositol bisphosphate, phosphatidylinositol triphosphate,ceramide phosphorylcholine, ceramide phosphorylethanolamine, ceramidephosphorylglycerol, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilinoleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, or a combination of two or more thereof.

Embodiment 123. The composition of any one of Embodiments 120 to 122,wherein the one or more zwitterionic surfactants comprise lecithin.

Embodiment 124. The composition of any one of Embodiments 120 to 123,wherein the one or more zwittterionic surfactants are present in thecomposition in an amount of at least about 10 wt. %.

Embodiment 125. The composition of any one of Embodiments 120 to 123,wherein the one or more zwitterionic surfactants are present in thecomposition in an amount of about 5 wt. % to about 25 wt. %.

Embodiment 126. The composition of any one of Embodiments 113 to 125,wherein the pH dependent release system comprises a carboxylic acidhaving at least 8 carbon atoms.

Embodiment 127. The composition of Embodiment 126, wherein thecarboxylic acid having at least 8 carbon atoms is present in thecomposition in an amount of at least about 5 wt. %.

Embodiment 128. The composition of Embodiment 126, wherein thecarboxylic acid having at least 8 carbon atoms is present in thecomposition in an amount of about 5 wt. % to about 50 wt. %.

Embodiment 129. The composition of any one of Embodiments 126 to 128,wherein the carboxylic acid having at least 8 carbon atoms is amonocarboxylic acid.

Embodiment 130. The composition of any one of Embodiments 126 to 129,wherein the carboxylic acid having at least 8 carbon atoms is selectedfrom the group consisting of as octenoic acid, decenoic acid,decadienoic acid, lauroleic acid, laurolinoleic acid, myristovaccenicacid, myristolinoleic acid, myristolinolenic acid, palmitolinolenicacid, palmitidonic acid, α-linolenic acid, stearidonic acid,dihomo-α-linolenic acid, eicosatetraenoic acid, eicosapentaenoic acid,clupanodonic acid, docosahexaenoic acid,9,12,15,18,21-tetracosapentaenoic acid,6,9,12,15,18,21-tetracosahexaenoic acid, myristoleic acid,palmitovaccenic acid, α-eleostearic acid, β-eleostearic acid, punicicacid, 7,10,13-octadecatrienoic acid, 9,12,15-eicosatrienoic acid,β-eicosatetraenoic acid, 8-tetradecenoic acid, 12-octadecenoic acid,linoleic acid, linolelaidic acid, γ-linolenic acid, calendic acid,pinolenic acid, dihomo-linoleic acid, dihomo-γ-linolenic acid,arachidonic acid, adrenic acid, osbond acid, palmitoleic acid, vaccenicacid, rumenic acid, paullinic acid, 7,10,13-eicosatrienoic acid, oleicacid, elaidic acid, gondoic acid, erucic acid, nervonic acid,8,11-eicosadienoic acid, mead acid, sapienic acid, gadoleic acid,4-hexadecenoic acid, petroselinic acid, and 8-eicosenoic acid, or acombination of two or more thereof.

Embodiment 131. The composition of any one of Embodiments 113 to 130,wherein the non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system further comprises:

-   -   (a) one or more polyacids,    -   (b) one or more water insoluble oligomers,    -   (c) one or more water insoluble polymers, or    -   (d) any combination thereof.

Embodiment 132. The composition of Embodiment 131, wherein the one ormore polyacids comprise a biocompatible fatty poly acid.

Embodiment 133. The composition of Embodiment 131, wherein the one ormore polyacids comprise glutaric acid (GA), poly(methacrylicacid-co-methyl methacrylate), or hypromellose phthalate (HPMC-P), or acombination of two or more thereof.

Embodiment 134. The composition of any one of Embodiments 131 to 133,wherein the one or more polyacids are present in the composition in anamount of about 1 wt. % to about 10 wt. %.

Embodiment 135. The composition of any one of Embodiments 131 to 134,wherein the one or more water insoluble oligomers comprise low molecularweight poly(hexyl substituted lactides) (PHLA), low molecular weightpolyethylene, polyvinyl chloride, ethyl cellulose, or acrylate polymersand copolymers thereof, or a combination of two or more thereof.

Embodiment 136. The composition of any one of Embodiments 131 to 135,wherein the one or more water insoluble oligomers are present in thecomposition in an amount of about 1 wt. % to about 5 wt. %.

Embodiment 137. The composition of any one of Embodiments 131 to 136,wherein the one or more water insoluble polymers comprise a copolymer ofethyl acrylate and methyl methacrylate, lactide-coglycolide, cellulose,or ethyl cellulose, or a combination of two or more thereof.

Embodiment 138. The composition of any one of Embodiments 131 to 137,wherein the one or more water insoluble polymers are present in thecomposition in an amount of about 1 wt. % to about 5 wt. %.

Embodiment 139. The composition of any one of Embodiments 113 to 138,wherein the non-aqueous pH dependent release system further comprisesone or more neutral lipids.

Embodiment 140. The composition of Embodiment 139, wherein the one ormore neutral lipids comprise one or more biocompatible oils.

Embodiment 141. The composition of Embodiment 140, wherein the one ormore biocompatible oils comprise peanut oil, canola oil, avocado oil,safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin A,vitamin D, vitamin E, animal oils, fish oils, or krill oil, or acombination of two or more thereof.

Embodiment 142. The composition of Embodiment 139, wherein the one ormore neutral lipids comprise a fatty acid ester.

Embodiment 143. The composition of Embodiment 142, wherein the fattyacid ester is a fatty acid methyl ester.

Embodiment 144. The composition of Embodiment 143, wherein the fattyacid methyl ester is methyl linolenate, methyl oleate, or methylpalmitate, or a combination of thereof.

Embodiment 145. The composition of any one of Embodiments 139 to 144,wherein the one or more neutral lipids are present in the composition inan amount of about 30 wt. % to about 75 wt. %.

Embodiment 146. A pharmaceutical composition comprising, consistingessentially of, or consisting of:

-   -   (a) a carrier composition according to any one of Embodiments        113 to 145; and    -   (b) one or more biologically active agents,    -   wherein a weight ratio of the carrier composition to the one or        more biologically active agents is between about 10:1 and about        1:2.

Embodiment 147. The pharmaceutical composition of Embodiment 146,wherein the one or more biologically active agents is suspended in thecarrier composition.

Embodiment 148. The pharmaceutical composition of Embodiments 146 or147, wherein the one or more biologically active agents are crystallinesolid particles.

Embodiment 149. The pharmaceutical composition of any one of Embodiments146 to 148, wherein the biologically active agent comprises at least oneagent selected from the group consisting of an acid-labilepharmaceutical agent, an anti-depressant, an anti-diabetic agent, ananti-epileptic agent, an anti-fungal agent, an anti-malarial agent, ananti-muscarinic agent, an anti-neoplastic agent, an immunosuppressant,an anti-protozoal agent, an anti-tussive, a neuroleptics, abeta-blocker, a cardiac inotropic agent, a corticosteroid, ananti-parkinsonian agent, a gastrointestinal agent, histamine, ahistamine receptor antagonist, a keratolytic, a lipid regulating agent,a muscle relaxant, a nitrate, an anti-anginal agent, a non-steroidalanti-inflammatory agent, a nutritional agent, an opioid analgesic, a sexhormone, a stimulant, a nutraceutical, a peptide, a protein, atherapeutic protein, a nucleoside, a nucleotide, DNA, RNA, aglycosaminoglycan, an acid-labile drug,(+)-N{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea,amylase, aureomycin, bacitracin, beta carotene, cephalosporins,chloromycetin, cimetidine, cisapride, cladribine, clorazepate,deramciclane, didanosine, digitalis glycosides, dihydrostreptomycin,erythromycin, etoposide, famotidine, a hormone, estrogen, insulin,adrenalin, heparin, lipase, milameline, novobiocin, pancreatin,penicillin salts, polymyxin, pravastatin, progabide, protease,quinapril, quinoxaline-2-carboxylic acid,[4-(R)carbamoyl-1-(S-3-fluorobenzyl-2-(S),7-dihydroxy-7-methyloctyl]amide,quinoxaline-2-carboxylicacid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amideranitidine, streptomycin, subtilin, sulphanilamide, a proton pumpinhibitors, esomeprazole, lansoprazole, minoprazole, omeprazole,pantoprazole and rabeprazole.

Embodiment 150. The pharmaceutical composition of any one of Embodiments146 to 149, wherein the one or more biologically active agents ishydrophobic.

Embodiment 151. The pharmaceutical composition of any one of Embodiments146 to 150, wherein the one or more biologically active agents includesan acid labile drug.

Embodiment 152. The pharmaceutical composition of Embodiment 151,wherein the acid-labile drug is selected from the group consisting ofheparin, insulin, erythropoietin, pancreatin, lansoprazole, omeprazole,pantoprazole, rabeprazole, penicillin salts, benzathine penicillin,polymyxin, sulphanilamide, and erythromycin.

Embodiment 153. The pharmaceutical composition of any one of Embodiments146 to 149, wherein the one or more biologically active agents includesa non-steroidal anti-inflammatory agent (NSAID).

Embodiment 154. The pharmaceutical composition of Embodiment 153,wherein the NSAID is selected from the group consisting of ibuprofen,piroxicam, salicylate, aspirin, naproxen, indomethacin, diclofenac,mefenamic acid, COX2 inhibitors, and any mixture thereof.

Embodiment 155. The pharmaceutical composition of Embodiment 154,wherein the NSAID is selected from the group consisting of aspirin,naproxen, indomethacin and mefenamic acid.

Embodiment 156. The pharmaceutical composition of Embodiment 154,wherein the NSAID is aspirin.

Other embodiments are set forth in the following claims.

1.-57. (canceled)
 58. A pharmaceutical carrier composition comprising:(a) a non-aqueous pH dependent release system comprising oleic acid; and(b) a non-aqueous pH dependent reassembly/assembly andreabsorption/absorption system comprising: (1) one or more nonionicsurfactants comprising polyethylene glycol (PEG) fatty acid esternonionic surfactants, PEG-8 caprylic/capric glyceride nonionicsurfactants, tocopherol PEG succinate nonionic surfactants, polyglycolmodified castor oil nonionic surfactants, polysorbate nonionicsurfactants, or a combination thereof, and (2) one or more neutrallipids comprising one or more biocompatible oils selected from peanutoil, canola oil, avocado oil, safflower oil, olive oil, corn oil,soybean oil, sesame oil, vitamin A, vitamin D, vitamin E, animal oils,fish oils, or krill oil, or a combination of two or more thereof,wherein: (i) the oleic acid is present in the carrier composition in anamount of about 5 wt. % to about 50 wt. %, the one or more nonionicsurfactants are present in the carrier composition in an amount of about0.05 wt. % to about 20 wt. %, and the one or more neutral lipids arepresent in the carrier composition in an amount of about 30 wt. % toabout 75 wt. %; (ii) the carrier composition is capable of adopting: (a)a low pH form at a pH less than or equal to about pH 3, and (b) a highpH form at a pH greater than about pH 3, and (iii) the carriercomposition is capable of: (a) releasing one or more biologically activeagents minimally from the low pH form of the carrier composition in alow pH environment; (b) either reassembling into the low pH form orassembling into a new low pH form; and (c) either reabsorbing the one ormore biologically active agents into the low pH form or the new low pHform.
 59. The composition of claim 58, wherein the composition protectsthe stomach from injury and/or protects the one or more biologicallyactive agents from degradation during duodenal reflux.
 60. Thecomposition of claim 58, wherein the non-aqueous pH dependentreassembly/assembly and reabsorption/absorption system further comprisesone or more zwitterionic surfactants, one or more anionic surfactants,one or more cationic surfactants, or any combination of two or morethereof; wherein: (a) the one or more zwitterionic surfactants comprise:(i) zwitterionic phospholipids, (ii) betaines, (iii) sulfobetaines, or(iv) any combination of two or more thereof; (b) the one or more anionicsurfactants comprise: (i) carboxylate anionic surfactants, (ii) sulfateanionic surfactants, (iii) sulfonates anionic surfactants, (iv)phosphate esters anionic surfactants, or (v) any combination of two ormore thereof; and (c) the one or more cationic surfactants comprisequaternary ammonium salts.
 61. The composition of claim 60, wherein: (a)the one or more zwitterionic phospholipids comprise phosphatidic acid,phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine,phosphatidylinositol, phosphatidylinositol phosphate,phosphatidylinositol bisphosphate, phosphatidylinositol triphosphate,ceramide phosphorylcholine, ceramide phosphorylethanolamine, ceramidephosphorylglycerol, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilinoleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, or a combination of two or more thereof;(b) the one or more anionic surfactants comprise sodium lauryl sulfate;sodium laureth sulfate, dioctyl sodium sulfosuccinate, or sodium dodecylsulfate; and (c) the one or more cationic surfactants comprisealkyltrimethylammonium chlorides or alkyltrimethylammonium bromides. 62.The composition of claim 61, wherein the one or more zwitterionicsurfactants are comprised in lecithin.
 63. The composition of claim 61,wherein: (a) the one or more nonionic surfactants are present in thecomposition in an amount of about 10 wt. % to about 20 wt. %; (b) theone or more zwitterionic surfactants are present in the composition inan amount of at least about 10 wt. %; (c) the one or more anionicsurfactants are present in the composition in an amount of at leastabout 5 wt. %; and (d) the one or more cationic surfactants are presentin the composition in an amount of at least about 5 wt. %.
 64. Thecomposition of claim 61, wherein: (a) the one or more nonionicsurfactants are present in the composition in an amount of between about0.05 wt. % and about 20 wt. %; (b) the one or more zwitterionicsurfactants are present in the composition in an amount of about 5 wt. %to about 25 wt. %; (c) the one or more anionic surfactants are presentin the composition in an amount of at least about 0.1 wt. % to about 5wt. %; and (d) the one or more cationic surfactants are present in thecomposition in an amount of at least about 0.1 wt. % to about 5 wt. %.65. The composition of claim 58, wherein the oleic acid is present inthe composition in an amount of between about 10 wt. % and about 50 wt.%, between about 15 wt. % and about 50 wt. %, or between about 20 wt. %and about 50 wt. %.
 66. The composition of claim 58, wherein thenon-aqueous pH dependent reassembly/assembly and reabsorption/absorptionsystem further comprises: (a) one or more polyacids comprising glutaricacid (GA), poly(methacrylic acid-co-methyl methacrylate), orhypromellose phthalate (HPMC-P), or a combination of two or morethereof, (b) one or more water insoluble oligomers comprising lowmolecular weight poly(hexyl substituted lactides) (PHLA), low molecularweight polyethylene, polyvinyl chloride, ethyl cellulose, or acrylatepolymers and copolymers thereof, or a combination of two or morethereof, (c) one or more water insoluble polymers comprising a copolymerof ethyl acrylate and methyl methacrylate, lactide-coglycolide,cellulose, or ethyl cellulose, or a combination of two or more thereof,or (d) any combination thereof.
 67. The composition of claim 66, whereinthe one or more polyacids are present in the composition in an amount ofabout 1 wt. % to about 10 wt. % or in an amount of about 1 wt. % toabout 5 wt. %.
 68. The composition of claim 66, wherein the one or morewater insoluble polymers are present in the composition in an amount ofabout 1 wt. % to about 5 wt. %.
 69. The composition of claim 58, furthercomprising less than 10 wt. % of one or more selected from the groupconsisting of (1) fatty acid salts, (2) secondary complexing agents, (3)protective agents, (4) excipients, (5) adjuvants, (6) drying agents, (7)antioxidants, (8) preservatives, (9) chelating agents, (10)viscomodulators, (11) tonicifiers, (12) flavorants and taste maskingagents, (13) colorants, (14) odorants, (15) opacifiers, (16) suspendingagents, and (17) binders.
 70. A pharmaceutical composition comprising:(a) a carrier composition according to claim 58; and (b) one or morebiologically active agents, wherein the weight ratio of the carriercomposition to the one or more biologically active agents is betweenabout 10:1 and about 1:2.
 71. The pharmaceutical composition of claim70, wherein the one or more biologically active agents is suspended inthe carrier composition.
 72. The pharmaceutical composition of claim 70,wherein the one or more biologically active agents are crystalline solidparticles.
 73. The pharmaceutical composition of claim 70, wherein thebiologically active agent comprises at least one agent selected from thegroup consisting of a non-steroidal anti-inflammatory agent, a peptide,and a protein.
 74. The pharmaceutical composition of claim 70, whereinthe one or more biologically active agents is hydrophobic.
 75. Thepharmaceutical composition of claim 70, wherein the one or morebiologically active agents comprises an acid labile drug.
 76. Thepharmaceutical composition of claim 75, wherein the acid-labile drug isselected from the group consisting of heparin, insulin, erythropoietin,pancreatin, lansoprazole, omeprazole, pantoprazole, rabeprazole,penicillin salts, benzathine penicillin, polymyxin, sulphanilamide, anderythromycin.
 77. The pharmaceutical composition of claim 70, whereinthe one or more biologically active agents comprises a non-steroidalanti-inflammatory agent (NSAID) selected from the group consisting ofibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin,diclofenac, mefenamic acid, COX2 inhibitors, and any mixture thereof.